Protein Families

Cu/Zn superoxide dismutases dismutate superoxide to hydrogen peroxide and oxygen using a copper catalytic site and a structural zinc. The family contains the cytosolic SOD1 enzymes of eukaryotes (S. cerevisiae SOD1, S. pombe sod1, human SOD1), extracellular and periplasmic Cu/Zn SODs, and the copper chaperones for SOD1 (CCS), whose SOD-like domain delivers copper to SOD1 but has no dismutase activity. PANTHER defines 17 subfamilies for this family, two of them named for the CCS chaperones (SF86 and SF101), but the PANTHER member inventory used here assigns no member to a subfamily, so this review works at family level.

Lipid kinases with a PI3K/PI4K catalytic domain. The family contains the class I PI3Ks (PIK3CA, PIK3CB, PIK3CD, PIK3CG), which make PI(3,4,5)P3 in receptor signaling; the class II PI3Ks (PIK3C2A, PIK3C2B, PIK3C2G); the class III PI3K VPS34 (PIK3C3), which makes PI3P for endosomal sorting and autophagy; and the type III PI4Ks, PI4KA (Stt4) and PI4KB (Pik1), which make PI4P at the plasma membrane and Golgi. Each lipid product is specific to a subfamily.

S-formylglutathione hydrolases release formate and glutathione from S-formylglutathione, the last step of glutathione-dependent formaldehyde detoxification. The family contains bacterial FrmB/FghA and the YeiG paralog (two PANTHER subfamilies), S. cerevisiae YJL068C, and human esterase D (ESD).

Phosphatidylserine decarboxylases (PSDs) are pyruvoyl-dependent enzymes that decarboxylate phosphatidylserine (PS) to phosphatidylethanolamine (PE). They are made as proenzymes that cleave themselves at a conserved GGST/LGST motif, and the serine at the cleavage site becomes the pyruvoyl prosthetic group. The family covers bacterial Psd (E. coli, B. subtilis, P. putida), the eukaryotic mitochondrial inner-membrane type I enzymes (yeast PSD1, S. pombe psd1, human PISD), and the PSD2-type enzymes. The PSD2 type includes long C2-domain proteins in fungi and plants (yeast PSD2, S. pombe psd3, plant PSD2/PSD3) and short Clostridium and Chlamydia Psd. S. pombe psd2 sits alone in SF19. The family also contains the Psilocybe/Amanita psiD/iboD enzymes (SF9). These have been recruited to decarboxylate L-tryptophan for psilocybin biosynthesis.

Small A-type carrier proteins (HesB/YadR/YfhF domain) with a C-terminal Cys-X-Cys motif plus a third conserved cysteine that bind iron or [2Fe-2S] clusters and deliver clusters to acceptor apoproteins, in particular in the late maturation of [4Fe-4S] proteins. The family contains proteobacterial IscA and its mitochondrial descendants ISCA1/ISA1 (SF41), the Suf-system carrier SufA (SF47), and a small plant ISCA-like 3 group (SF60). Whether a given A-type protein acts mainly as an iron donor, an alternative scaffold or a downstream cluster carrier is still debated.

Aldose 1-epimerases (mutarotases) interconvert the alpha and beta anomers of aldoses. Galactose mutarotase converts beta-D-galactose to the alpha anomer used by galactokinase, the first step of the Leloir pathway. The family contains the standalone bacterial GalM and animal GALM enzymes, a Levilactobacillus maltose epimerase, uncharacterized yeast paralogs (YHR210C, YNR071C), and fungal putative epimerases in SF6. Fungal Gal10 carries its mutarotase as a domain fused to UDP-glucose 4-epimerase and is not in this family.

The family contains U-type proteins involved in iron-sulfur protein maturation. Bacterial IscU, the N-terminal scaffold domain of NifU and eukaryotic ISU/ISCU assemble and deliver transient clusters. The Bacillus subtilis SufU member O32163 instead has strong biochemical and genetic support for zinc-dependent sulfur transfer from SufS toward the SufBCD assembly machinery, alongside earlier reports of in vitro cluster reconstitution and delivery. Similar folds therefore do not establish the same molecular activity in every member. PANTHER subfamily coverage remains incompletely resolved: E. coli IscU P0ACD4 is classified in SF8 in the PANTHER19 sequence file rather than the IscU-named SF26, and the committed inventory lacks subfamily assignments. No functionally precise subfamily boundary is inferred from names alone.

Phosphoribosylformylglycinamidine (FGAM) synthase, also called FGAR amidotransferase (FGARAT), catalyses step 4 of de novo IMP biosynthesis: the ATP- and glutamine-dependent conversion of formylglycinamide ribonucleotide (FGAR) to formylglycinamidine ribonucleotide (FGAM). The members of this family that carry out the reaction are the large single-chain enzymes (E. coli and Pseudomonas PurL, S. cerevisiae Ade6, S. pombe ade3, animal PFAS, plant At1g74260), in which a glutaminase domain supplies ammonia to the synthetase domain within one polypeptide. The family inventory also holds the separate PurQ glutaminase subunits of archaeal small-PurL systems and herpesvirus tegument proteins (Epstein-Barr virus BNRF1, KSHV ORF75 and related antigens) that are homologous to FGAM synthase.

Phage-type RNA polymerases are single-chain enzymes that synthesize RNA from DNA templates. Mitochondrial members combine the conserved polymerase core with lineage-specific targeting and transcription-factor interactions.

TRAF proteins organize receptor-associated signaling assemblies through conserved interaction domains and variable amino-terminal regions. Their roles include recruiting ubiquitin-system components and controlling inflammatory and survival pathways.

Mre11/Rad32 proteins are DNA-end-processing nucleases that cooperate with Rad50-containing complexes in DNA repair. Their conserved nuclease functions are coupled to DNA-end recognition and organism-specific checkpoint and meiotic programs.

UDP-glucose-dependent glycogen synthases of fungi and animals (glycosyltransferase family 3). They extend alpha-1,4-glucan chains on glycogenin-primed glycogen and are regulated by phosphorylation and glucose-6-phosphate. Fungi have GSY1/GSY2-type paralogs (SF3); vertebrates have the muscle (GYS1, SF2) and liver (GYS2, SF1) isoforms.

Cyclins are regulatory proteins that control cyclin-dependent kinases. Different cyclin groups specify cell-cycle transitions and other transcriptional or regulatory programs through distinct partners and expression patterns.

PTHR10192 contains MoeA-type molybdopterin molybdotransferases, which insert molybdate into adenylyl-molybdopterin and release AMP to form the Mo-molybdopterin cofactor. Bacterial MoeA proteins act alone. Eukaryotic members (plant CNX1, insect cinnamon, metazoan gephyrin) fuse the MoeA region to a MogA-type adenylyltransferase region and catalyse both final steps. Metazoan gephyrin has also acquired a scaffolding role, clustering glycine and GABA-A receptors at inhibitory synapses.

RasGAP-related proteins accelerate GTP hydrolysis by small GTPases rather than hydrolyzing free GTP as the principal catalyst themselves. Ras versus Rap preference and regulatory localization vary across the group.

FGGY-family carbohydrate kinases contain paired domains that support ATP-dependent phosphorylation of carbohydrate substrates. Members differ in the small molecules they recognize and the metabolic pathways they serve.

Presenilins are the catalytic subunits of gamma-secretase, the intramembrane-cleaving aspartyl protease complex that also contains nicastrin, APH-1 and PEN-2. Two aspartates, in transmembrane segments 6 and 7 (the TM7 one in a GxGD motif), form the active site. The complex cleaves the membrane stubs left after ectodomain shedding of many type I transmembrane proteins. In Notch signaling this is the S3 cleavage that releases the Notch intracellular domain; in APP processing it produces amyloid-beta. Presenilins are found throughout eukaryotes. Animals have presenilin/gamma-secretase and Notch, but the social amoeba Dictyostelium has a highly diverged, catalytically active gamma-secretase and no Notch or APP. Plants have presenilin homologs whose gamma-secretase activity has not been shown. Vertebrates have two paralogs (PSEN1, PSEN2). C. elegans has three: SEL-12 and HOP-1, which act redundantly in LIN-12/GLP-1 Notch signaling, and the sperm-specific SPE-4.

PRPP synthases transfer the beta,gamma-diphosphate of ATP to ribose 5-phosphate, making phosphoribosyl diphosphate for nucleotide, histidine, tryptophan and NAD synthesis. The family contains the bacterial and plant Prs enzymes, the five S. cerevisiae PRS paralogs (which form heteromeric complexes), S. pombe PRPP synthases, and human PRPS1-3. It also contains the non-catalytic PRPP synthase-associated proteins PRPSAP1 and PRPSAP2, which bind and regulate PRPS.

Selenophosphate synthetases generate the selenium donor for selenocysteine biosynthesis, catalysing selenophosphate formation from hydrogen selenide and ATP (EC 2.7.9.3). Catalysis runs through a nucleophile at the tip of a glycine-rich loop, and that nucleophile is itself selenocysteine in the human catalytic paralog SEPHS2 -- a selenoprotein required to make selenoproteins. Bacterial SelD uses a cysteine at the equivalent position instead, so the family tolerates either chalcogen nucleophile. The human paralog SEPHS1 has substituted that position with threonine. Its selenophosphate-synthase role is contested: UniProt records that "several studies suggest that it does not act as a selenophosphate synthase in vivo", and its current recommended name is Zincore component SEPHS1, reflecting a characterised role stabilising zinc-finger transcription factors on DNA rather than in selenium metabolism.

Claisen-condensation enzymes of the DRE-TIM metallolyase superfamily, which add acetyl-CoA to a 2-oxo acid. Subfamilies differ in the 2-oxo acid: 2-oxoglutarate for homocitrate synthase (lysine biosynthesis by the alpha-aminoadipate pathway: S. cerevisiae LYS20/LYS21, S. pombe lys4; SF48, SF63); 2-oxoisovalerate for 2-isopropylmalate synthase (leucine biosynthesis; LeuA, the largest subfamily, SF9); omega-methylthio-2-oxoalkanoates for plant MAM enzymes (glucosinolate chain elongation; SF60 and the directly characterized Brassica BjMAM1-A member of SF73); and pyruvate for citramalate synthase (CimA; SF57).

Antizymes are polyamine-induced inhibitors of ornithine decarboxylase. Their synthesis needs a polyamine-stimulated +1 ribosomal frameshift; they bind ODC monomers, block dimerization and target ODC for ubiquitin-independent proteasomal degradation. The family contains the metazoan antizymes 1-3 and the fungal antizymes, such as S. pombe spa1 and S. cerevisiae OAZ1.

This transporter family includes membrane proteins with citrate-transporter-like architecture and diverse solute preferences. Fungal SPX-containing members connect transport with phosphate homeostasis.

P-loop kinases that phosphorylate ribose-containing metabolites or pantothenate. The family contains the uridine-cytidine kinases (S. cerevisiae URK1, S. pombe urk1, human UCK1/UCK2/UCKL1, bacterial Udk), the nicotinamide/nicotinate riboside kinases of NAD salvage (S. cerevisiae NRK1, S. pombe nrk1, human NMRK1/NMRK2), the bacterial type I pantothenate kinases (CoaA), and S. cerevisiae YFH7, a kinase of unknown substrate.

PTHR10291 is the cis-prenyltransferase (Z-prenyltransferase) family, the UPP synthase-like fold (InterPro IPR001441). Every characterized member adds isopentenyl diphosphate units in the cis configuration onto an allylic diphosphate primer to make a cis-polyprenyl diphosphate. Chain length, primer stereochemistry and oligomeric state vary by lineage. Bacterial UppS (E. coli IspU, Micrococcus luteus, Bacillus subtilis, Staphylococcus aureus) is a soluble Mg2+-dependent homodimer that makes C55 undecaprenyl diphosphate from (2E,6E)-farnesyl diphosphate, the precursor of the undecaprenyl-phosphate glycan carrier. Mycobacteria have a two-enzyme route: Rv1086 makes (2Z,6E)-farnesyl diphosphate and Rv2361c extends it to C50 decaprenyl diphosphate. Archaeal members make C55 from geranylgeranyl diphosphate. In eukaryotes, the catalytic subunit (human DHDDS, yeast RER2/SRT1) makes long-chain dehydrodolichyl diphosphate at the ER for dolichyl-phosphate synthesis, usually with a NUS1/NgBR partner subunit from a different family. Plant plastid paralogs make short or medium cis-prenyl diphosphates.

Type I phosphomannose isomerases are zinc-dependent cupin-fold enzymes. They interconvert D-fructose 6-phosphate and D-mannose 6-phosphate. In the biosynthetic direction they take fructose 6-phosphate from glycolysis and make mannose 6-phosphate, the committed precursor of GDP-mannose and dolichyl-phosphate mannose. In the catabolic direction they let exogenous mannose enter glycolysis. The family covers bacterial ManA (E. coli, M. tuberculosis) and the eukaryotic enzymes: S. cerevisiae PMI40, S. pombe SPBC2G2.16 (pmi40/mpi1), Candida PMI1, human MPI, and the Arabidopsis PMI1 and PMI2 paralogs.

Fold-type II PLP enzymes that carry out beta-replacement on serine-derived substrates. The family contains cystathionine beta-synthase (CBS; S. cerevisiae CYS4, human CBS), which condenses serine and homocysteine in reverse transsulfuration; the bacterial and plant O-acetylserine sulfhydrylases (bacterial CysK and CysM, plant OAS-TL isoforms), which make cysteine; threonine synthases (ThrC, SF5); and bacterial L-cysteine desulfhydrases and siderophore-precursor synthases (SbnA). PANTHER subfamily SF194, despite its CYSTATHIONINE BETA-SYNTHASE name, holds both the eukaryotic CBS proteins and the bacterial CysK (cysteine synthase A) proteins. SF162 contains OAS-active CysM proteins and the OPS/CysO-dependent M. tuberculosis CysM; the CysM name does not establish substrate choice.

PI-PLCs hydrolyse phosphatidylinositol 4,5-bisphosphate to diacylglycerol and inositol 1,4,5-trisphosphate. The family contains the animal beta, gamma, delta, epsilon and zeta isozymes, which differ in regulatory domains and activators (G proteins, receptor tyrosine kinases, Ca2+, Ras), and the single fungal PLC (S. cerevisiae PLC1, S. pombe plc1).

PTHR10340 is a metallo-dependent phosphodiesterase/phosphohydrolase family whose reviewed members separate into metazoan and amoebozoan sphingomyelin or cyclic GMP-AMP phosphodiesterases and a fungal Ppn1 clade that degrades inorganic polyphosphate. PAINT correctly confines the fungal-type vacuole, endopolyphosphatase, exopolyphosphatase and polyphosphate catabolism assertions to the fungal PTHR10340:SF55 Ppn1 subfamily, while IRDs on the fungal node stop extracellular and broad phosphoric-diester-hydrolase terms from the metazoan acid-sphingomyelinase side of the tree.

Thymidylate kinases are small P-loop nucleoside monophosphate kinases. They phosphorylate dTMP to dTDP using ATP, the step shared by the de novo route (from thymidylate synthase) and the salvage route (from thymidine kinase) to dTTP. The family includes bacterial Tmk (E. coli, B. subtilis, M. tuberculosis), eukaryotic TMPK (S. cerevisiae CDC8, S. pombe tmp1, human DTYMK) and several viral thymidylate kinases. Many members also phosphorylate dUMP weakly, and purified yeast Cdc8 has some nucleoside-diphosphate kinase activity in vitro. One vertebrate member is functionally distinct: the mitochondrial UMP-CMP kinase 2 (CMPK2). It phosphorylates dUMP, dCMP, CMP and UMP, has interferon-induced antiviral roles, and PAINT treats it as having lost dTMP kinase activity.

A large glycoside hydrolase family 13 (GH13) family whose members share the (beta/alpha)8 alpha-amylase catalytic barrel but act on different bonds and substrates. It includes endo-acting alpha-amylases (E. coli MalS, Bacteroides SusG), exo-acting alpha-1,4-glucosidases and maltases (E. coli MalZ, yeast MAL12/MAL32), alpha-1,6-specific isomaltases (yeast IMA1-IMA5), trehalose 6-phosphate hydrolases (E. coli TreC), neopullulanases and cyclomaltodextrinases, and two isomerase-type transglycosylases of trehalose synthesis: TreY maltooligosyl trehalose synthase (SF216) and TreS maltose alpha-D-glucosyltransferase (SF219). The vertebrate rBAT/SLC3A1 heavy chain of heteromeric amino-acid transporters keeps the GH13 fold but has no detected glucosidase activity. Activity therefore has to be read per clade, not inherited from the family.

The SLC10 family comprises the sodium-coupled bile salt and sulfoconjugate carriers of the bile acid:sodium symporter (BASS) fold, plus several members whose cargo is unknown. The two best-characterised human members work at opposite poles of polarised epithelia: SLC10A1/NTCP takes conjugated bile salts up across the hepatocyte basolateral membrane, and SLC10A2/ASBT reclaims them across the ileal apical brush border. SLC10A6/SOAT transports 3'- and 17'-monosulfated steroids rather than ordinary bile acids, though it does carry taurolithocholate. SLC10A4 and SLC10A5 are orphan carriers with no identified substrate, and SLC10A7 is the most divergent member: it sits in the Golgi, no transport activity has been demonstrated for it, and its reported biology is calcium homeostasis and glycosylation. The plant and bacterial members (BASS1-6, Acr3-related arsenite permeases) carry different cargo again, so the family as a whole is held together by fold rather than by substrate.

The small thioredoxin-fold [2Fe-2S] subunit of the NADH-oxidising (N) module of proton-pumping NADH:quinone oxidoreductases: bacterial NuoE (Nqo2 in Thermus and Paracoccus) and mitochondrial NDUFV2. It binds one binuclear cluster, N1a, through four conserved cysteines and packs against the 51 kDa flavoprotein (NuoF/NDUFV1, PANTHER PTHR43578 or PTHR11780 depending on the classification source). N1a lies within electron-transfer distance of the FMN but on the side opposite the main iron-sulfur wire; it is reduced rapidly by NADH via the flavin in E. coli complex I and has been proposed to act as an antioxidant electron sink. Loss of the N1a ligands in E. coli also depletes cluster N1b on NuoG and destabilises the complex, so the subunit is structurally as well as redox-functionally important. Every reviewed member in the fetched slice, from Aquifex, Thermus, proteobacteria, Mycobacterium and Rickettsia to plants, fungi, amoebae and animals, is a complex I subunit in a single subfamily.

Glyoxalase I isomerizes the hemithioacetal of methylglyoxal and glutathione to S-D-lactoylglutathione, the first step of glyoxalase-dependent methylglyoxal detoxification. The family contains the metal-dependent glyoxalase I enzymes of bacteria, fungi (S. cerevisiae GLO1, S. pombe glo1), plants and animals (GLO1).

Arthropod cuticle proteins contribute to extracellular cuticular structures, with sequence groups associated with different tissues and developmental stages. Rebers-Riddiford chitin-binding signatures characterize the cuticle-protein branch represented by Drosophila Lcp3.

SERINC/Tms proteins are multipass membrane proteins associated with membrane-lipid organization. Mammalian SERINC3 and SERINC5 have experimentally characterized lipid-scrambling and antiviral functions, while other members are less specifically characterized.

The family contains 5-hydroxyisourate (HIU) hydrolases, which hydrolyse the urate oxidase product in purine/urate catabolism (bacterial PucM, S. pombe SPCC285.04, vertebrate URAH), and vertebrate transthyretin (TTR), a plasma thyroxine- and retinol-binding transport protein that evolved from an HIU hydrolase and has no hydrolase activity.

Large eukaryotic family built on the M28 zinc-metallopeptidase fold (protease-associated domain + M28 peptidase domain + transferrin-receptor-like dimerisation domain). It spans functionally very different groups that share the fold but not the chemistry: (1) active binuclear-zinc carboxypeptidases - glutamate carboxypeptidase II (FOLH1/GCPII/PSMA, the best-characterized member, a membrane glutamate carboxypeptidase acting on N-acetyl- aspartyl-glutamate and folyl-poly-gamma-glutamates), NAALAD2, and the related ileal aminopeptidase NAALADL1; (2) the plant AMP1/LAMP1/VP8 clade of putative glutamate carboxypeptidases controlling meristem maintenance; (3) transferrin receptors TFRC/TFR2, which lost peptidase activity and repurposed the ectodomain fold for transferrin binding and endocytic iron import; (4) fungal TRE1/TRE2 and VPS70 trafficking-related proteins; and (5) the vertebrate pseudoenzyme NAALADL2, which retains the fold but has a degenerate active site (the GCPII catalytic-glutamate motif SW-DAEE is SW-GGTA in human NAALADL2) and no established molecular function. The family is therefore a showcase for both taxon-aware and activity-aware PAINT curation: catalytic terms are safe only on the clades that kept the catalytic machinery.

ER membrane-bound O-acyltransferases (MBOAT) that esterify neutral lipids with acyl-CoA. The family contains the sterol O-acyltransferases (animal SOAT1/2, fungal ARE1/ARE2 and S. pombe are1/are2), which make sterol esters, and DGAT1 of animals and plants, which makes triacylglycerol from diacylglycerol.

JAMM/MPN-family proteins occur in protein-modification and proteostasis complexes. Catalytic members use metal-dependent hydrolysis, but modifier specificity and activity depend on the protein and its complex context.

Choline/ethanolamine phosphotransferases use activated CDP-aminoalcohol donors to synthesize membrane phospholipids. The family contains choline-selective enzymes, ethanolamine-selective enzymes and dual-specificity CEPT enzymes. Donor specificity and the lipid acceptor define the reaction more precisely than the shared membrane phosphotransferase fold.

Thioredoxin-dependent peroxiredoxins of the PRX5 (type II) class reduce hydrogen peroxide and alkyl hydroperoxides through a peroxidatic cysteine and an intramolecular resolving cysteine. The family contains S. cerevisiae AHP1, human PRDX5, bacterial and plant type II Prx, and S. pombe pmp20 (SF39), which has lost the resolving cysteine and shows no detectable peroxidase activity.

Lysophosphatidic acid acyltransferases transfer an acyl chain from acyl-CoA or acyl-ACP to the sn-2 position of lysophosphatidic acid, making phosphatidic acid for glycerolipid synthesis. The family contains bacterial PlsC, fungal SLC1 (S. cerevisiae SLC1, S. pombe SPAC1851.02), plant LPAT1, and animal AGPAT1/2.

GHMP-kinase family enzymes that phosphorylate sugars. Most members are galactokinases (SF7), which make galactose 1-phosphate in the Leloir pathway: bacterial GalK, S. cerevisiae GAL1, S. pombe gal1 and human GALK1. SF7 also contains S. cerevisiae GAL3, a catalytically inactive paralog that acts as the galactose sensor of the GAL switch. Smaller subfamilies are a heptose 7-phosphate kinase (SF9) and plant galacturonokinase (SF6).

Eukaryotic phosphomannomutases belong to the haloacid dehalogenase (HAD) superfamily, subfamily IIB. They are Mg2+-dependent enzymes with an aspartate nucleophile, and they interconvert mannose 6-phosphate and alpha-D-mannose 1-phosphate using glucose 1,6-bisphosphate as activator. In the biosynthetic direction they make the mannose 1-phosphate that GDP-mannose pyrophosphorylase converts to GDP-mannose, the precursor of dolichyl-phosphate mannose and of all mannosylation in the secretory pathway. Members include S. cerevisiae SEC53, S. pombe pmm1, Candida PMM1, plant and protist PMMs, and the vertebrate paralogs PMM2 (the PMM2-CDG gene) and PMM1. These are unrelated to the bacterial alpha-D-phosphohexomutase-type phosphomannomutases.

DTD-family enzymes remove inappropriate amino acids from aminoacyl-tRNAs, providing a trans-editing checkpoint during translation. The characterized DTD mechanism rejects L-chiral amino acids and can also act on glycine-charged tRNAs; tRNA identity helps distinguish productive proofreading from misediting. The historical D-tyrosyl name is narrower than the established substrate class.

This chemokine-receptor family includes receptors with different chemokine specificities and signaling outputs. CXCR3 recognizes C-X-C chemokines, but other branches recognize C-C or XC ligands, and atypical receptors handle chemokines without the same canonical signaling response. Even CXCR3 splice isoforms can differ in their effects on cell migration and proliferation.

PTHR10491 groups extended short-chain dehydrogenase/reductase (SDR) proteins of the RmlD type. In bacteria the members are dTDP-4-dehydrorhamnose reductases (RmlD, EC 1.1.1.133) that reduce dTDP-4-dehydro-beta-L-rhamnose with NAD(P)H to dTDP-L-rhamnose, the last step of the RmlABCD pathway; Salmonella, M. tuberculosis and E. coli RmlD are the characterised examples, and the catalytic Tyr/Lys pair and Mg(2+)-dependent dimer interface are conserved. Antibiotic clusters contain RmlD-like 4-ketoreductases for other deoxysugars (NovS, OleU, StrL). The eukaryotic branch is methionine adenosyltransferase 2 subunit beta (MAT2B/MATbeta), a non-catalytic regulatory subunit that binds MAT2A and modulates S-adenosylmethionine synthesis while keeping the SDR fold. Plants carry the bifunctional NRS/ER epimerase-reductase. Bacteria also have uncharacterised RmlD-like paralogs outside rhamnose clusters (P. aeruginosa PA4069, P. putida PP_0500). PANTHER has a single subfamily, SF4, whose name (METHIONINE ADENOSYLTRANSFERASE 2 SUBUNIT BETA) describes only the eukaryotic branch.

The family is defined by the PurM fold (Pfam AIRS and AIRS_C). PurM, AIR synthetase or phosphoribosylformylglycinamidine cyclo-ligase (EC 6.3.3.1), uses ATP to close the imidazole ring of FGAM and give 5-aminoimidazole ribonucleotide, step 5 of de novo purine synthesis. Most members are standalone bacterial and archaeal PurM enzymes and plant plastid PUR5. PANTHER classifies whole proteins, so two multifunctional eukaryotic fusions are also in this family. In fungi, ADE5,7 (S. cerevisiae) and ade1 (S. pombe) join an N-terminal PurD-type GAR synthetase to the AIR synthetase. In animals, GART (human, mouse, chicken, Drosophila ade3) adds a C-terminal PurN-type GAR transformylase as well. Those extra domains are not homologous to PurM. Their standalone counterparts are classified in PTHR43472 (PurD) and PTHR43369 (PurN).

Medium (mu) subunits of eukaryotic heterotetrameric adaptor protein (AP) complexes (AP-1 through AP-4) and monomeric stonin endocytic adaptors (STON1, STON2, Drosophila stoned-B, C. elegans UNC-41). Family members share an N-terminal longin-like domain (which incorporates into the AP heterotetramer core in AP1M-AP4M or is replaced by a proline-rich/SHD region in stonins) and a C-terminal beta-sandwich mu-homology domain (MHD, IPR028565) that binds tyrosine-based (YxxPhi) or cargo-specific sorting motifs in the cytosolic tails of transmembrane cargo proteins.

Ribokinase-fold kinases that phosphorylate pyridoxal, pyridoxine and pyridoxamine to their 5'-phosphates in the vitamin B6 salvage pathway. The family contains bacterial PdxK (SF15) and PdxY (SF2), human PDXK, S. cerevisiae BUD16, the S. pombe paralogs SPCC18.10 and SPAC6F6.11c, and S. cerevisiae BUD17.

GNAT acetyl- and acyltransferases. SAT1 (SSAT) acetylates spermidine and spermine at N1, the rate-limiting step of polyamine catabolism and export. The family also contains SAT2 (thialysine N-epsilon-acetyltransferase), SATL1, invertebrate GNATs of unknown substrate, and plant tyramine N-feruloyltransferases.

SmG/Lsm7-family proteins are small RNA-associated subunits of heptameric ribonucleoprotein rings. SmG participates in the canonical Sm ring of several spliceosomal snRNPs. Lsm7 instead participates in Lsm complexes, including the U6-associated ring and the cytoplasmic mRNA-decapping ring.

Polytopic ER membrane NADPH-dependent reductases. Two activities sit in separate subfamilies: steroid 5-alpha-reductases (SRD5A1, SRD5A2, plant DET2), which reduce testosterone and other 3-oxo-delta4 steroids; and very-long-chain enoyl-CoA reductases (S. cerevisiae TSC13, S. pombe tsc13, human TECR, Arabidopsis ECR), the fourth step of each fatty-acid elongation cycle.

The bifunctional glycogen debranching enzyme of fungi and animals has a 4-alpha-glucanotransferase domain that moves a maltotriosyl unit from a phosphorylase-limit branch to the main chain, and an amylo-alpha-1,6-glucosidase domain that releases the remaining branch-point glucose.

UDP-GlcNAc:dolichyl-phosphate N-acetylglucosamine-1-phosphate transferases catalyse the first, tunicamycin-sensitive step of dolichol-linked oligosaccharide assembly on the cytoplasmic face of the ER (S. cerevisiae ALG7, S. pombe gpt2, human DPAGT1).

Class I 3-hydroxy-3-methylglutaryl-CoA reductases reduce HMG-CoA to mevalonate with two NADPH, the rate-limiting step of the mevalonate pathway. Canonical sterol-pathway members are ER membrane enzymes with a sterol-sensing membrane domain and a cytosolic catalytic domain, while some fungal secondary-metabolite clusters encode shorter catalytic-domain paralogs. The family contains S. cerevisiae HMG1/HMG2, S. pombe hmg1, human HMGCR and plant HMGRs.

ATP-dependent sugar and nucleoside kinases of the PfkB (ribokinase-like) fold, with a Rossmann-like catalytic domain and a beta-sheet lid that forms a beta-clasp dimer. Characterized members include ribokinases (RbsK, RBKS), nucleoside and pseudouridine kinases, 2-dehydro-3-deoxygluconokinase (KdgK), ketohexokinase (KHK) and the sulfofructose kinase YihV of the sulfoglycolytic Embden-Meyerhof-Parnas pathway, which phosphorylates 6-deoxy-6-sulfo-D-fructose at C1 and recognises the substrate sulfonate through a Lys-Asn-Arg triad. The local member inventory lists 32 reviewed members, 31 in the large ribokinase subfamily SF166 and YihV alone in SF157 (SULFOFRUCTOSE KINASE).

Carbohydrate esterase family 4 metalloenzymes that remove N-acetyl or N-formyl groups from amino-sugar polymers or lipid-linked sugars. The family contains fungal chitin deacetylases (S. cerevisiae CDA1/CDA2, which make chitosan in the ascospore wall; Cryptococcus CDA1-3), bacterial peptidoglycan deacetylases (PgdA, PdaA), polysaccharide deacetylases, and the ArnD formyl-arabinose deformylase of lipid A modification (the largest subfamily).

UCH-family cysteine proteases hydrolyze bonds at the ubiquitin C terminus. Their conserved catalytic framework serves different biological settings: small-conjugate processing, proteasome-associated deubiquitination and chromatin-associated deubiquitination. Regulatory extensions and partner complexes help determine substrate access.

RP/EB-related proteins use a calponin-homology region to associate with microtubules. Canonical end-binding proteins organize growing microtubule ends and recruit partner proteins, while specialized members can connect stable microtubule bundles to other cellular structures. The fly Mst27D example links nuclear pores to bundled microtubules during sperm nuclear elongation.

Copper amine oxidases oxidatively deaminate primary amines, producing an aldehyde, ammonia and hydrogen peroxide through copper/topaquinone-dependent chemistry. Family members differ in their preferred monoamine, diamine or polyamine substrates and in whether they act intracellularly, at membranes or extracellularly.

Class II aldolase-fold dehydratases that convert 5-methylthioribulose 1-phosphate to 2,3-diketo-5-methylthiopentyl 1-phosphate in the methionine salvage (MTA) cycle. The family contains bacterial MtnB, S. cerevisiae MDE1, S. pombe mde1, and human APIP (which also inhibits apoptosis), plus the uncharacterized S. pombe paralog SPAC9.06c (SF10).

HEAT-repeat regulatory scaffolds organize phosphatase complexes. PP2A A subunits assemble catalytic and regulatory partners; the retrieved family also includes PP4 regulatory proteins. Scaffold binding is distinct from catalytic dephosphorylation.

CSL proteins are sequence-specific DNA-binding transcription factors with a Rel-homology/beta-trefoil architecture. They recognise the GTGGGAA-type CSL response element and act as repressors or activators depending on the cofactors they recruit. In animals, the canonical CSL proteins (human and mouse RBPJ, Drosophila Suppressor of Hairless, C. elegans LAG-1) are the nuclear effectors of Notch signalling. The Notch intracellular domain binds CSL through its RAM and ankyrin regions and recruits Mastermind to form the activating ternary complex. The family is older than Notch. Fission yeast has two CSL proteins, Cbf11 and Cbf12, although fungi have no Notch pathway. Cbf11 binds the canonical CSL element and regulates cell adhesion and division. Vertebrates also have the RBPJ paralogue RBPJL (RBP-L), a pancreatic acinar component of the PTF1 complex that does not bind the Notch intracellular domain. Its activity is therefore Notch-independent.

Peptide amidation proceeds through monooxygenase and lyase reactions, carried in separate proteins or combined in bifunctional PAM. Copper/ascorbate-dependent monooxygenase chemistry and PAL lyase chemistry reside in different structural modules.

Typical 2-Cys peroxiredoxins reduce hydrogen peroxide, alkyl hydroperoxides and peroxynitrite with a peroxidatic and an intersubunit resolving cysteine, and are recycled by thioredoxin (or AhpF in bacteria). Several eukaryotic members switch to a chaperone function on hyperoxidation. The family contains bacterial AhpC, S. cerevisiae TSA1/TSA2, S. pombe tpx1, mitochondrial PRDX3-type enzymes, and human PRDX1, PRDX2 and PRDX4.

Class I aldolases that move a dihydroxyacetone unit from sedoheptulose 7-phosphate to glyceraldehyde 3-phosphate in the non-oxidative pentose phosphate pathway. The family contains bacterial TalA/TalB, S. cerevisiae TAL1 and NQM1, S. pombe tal1 and human TALDO1, and the bacterial fructose-6-phosphate aldolases (Fsa), which cleave fructose 6-phosphate without a phosphorylated donor acceptor pair. Subfamily SF40 also holds the 6-deoxy-6-sulfo-D-fructose transaldolases (EC 2.2.1.14) of the sulfo-TAL (sulfo-SFT) sulfoquinovose degradation pathway, SqvA of Bacillus megaterium and SftT of Bacillus aryabhattai, which transfer the dihydroxyacetone unit of sulfofructose to glyceraldehyde 3-phosphate or erythrose 4-phosphate, releasing 3-sulfolactaldehyde.

The family is built around the dephospho-CoA kinase (DPCK, CoaE) domain, which phosphorylates the 3'-hydroxyl of dephospho-CoA in the last step of coenzyme A synthesis. Bacteria, plants and fungi mostly have a standalone CoaE (E. coli CoaE, S. cerevisiae CAB5, S. pombe SPCC14G10.01). Animals fuse a phosphopantetheine adenylyltransferase (PPAT) domain to the kinase in the bifunctional CoA synthase COASY, which catalyses the last two steps. PANTHER classifies whole proteins, so the PPAT-only relatives of the COASY PPAT region are placed in this family as well: budding-yeast CAB4, fission-yeast SPAC1F12.08, plant COAD/PPAT proteins and an archaeal CoaD (Thermococcus TK2128). These carry only the cytidylyltransferase-like PPAT domain and no kinase domain. Vertebrates also have DCAKD, a kinase-domain protein of uncertain function.

This group contains bacterial ribosomal S1 proteins alongside S1-domain proteins such as Tex and other RNA-associated proteins. RNA-binding architecture is shared more broadly than incorporation into a ribosomal subunit.

CTP:phosphocholine cytidylyltransferases make CDP-choline, the rate-limiting step of phosphatidylcholine synthesis by the Kennedy pathway. They are amphitropic enzymes activated by binding to lipid-packing defects in the nuclear envelope and ER through an amphipathic helix. The family contains S. cerevisiae PCT1, the S. pombe CCT (SPCC1827.02c), human PCYT1A/PCYT1B, and plant CCT1/CCT2.

FAD-dependent amine oxidases of the monoamine oxidase/LSD fold. The family is very diverse: polyamine oxidases (S. cerevisiae FMS1, human PAOX and SMOX), lysine-specific histone demethylases (KDM1A, KDM1B, Arabidopsis FLD/LDL), L-amino-acid oxidases (snake venom LAAO, IL4I1), and bacterial flavin monooxygenases that oxidatively decarboxylate amino acids (P. putida DavB lysine 2-monooxygenase, IaaM tryptophan 2-monooxygenase).

uL4-family proteins are structural components of the large ribosomal subunit. Bacterial and organellar homologues share the ribosome-associated role, but the cellular location and translation system depend on lineage and targeting. Pombe Yml6 belongs to the mitochondrial uL4 group.

Non-canonical radical-SAM [4Fe-4S] enzymes that carry out the first step of diphthamide synthesis on translation elongation factor 2. They cleave S-adenosylmethionine at the Cγ-S bond and transfer the 3-amino-3-carboxypropyl (ACP) group to the target histidine. Archaea have a single Dph2 that works as a homodimer, and Pyrococcus horikoshii Dph2 alone catalyses the step in vitro. Eukaryotes have two paralogs, Dph1 and Dph2, which form an obligate heterodimer. The Dph1 cluster is catalytic, and the Dph2 cluster is needed for the physiological Dph3/Cbr1/NADH reducing system to reduce the Dph1 cluster. Archaeal Dph2 is closer in sequence to eukaryotic Dph1 than to Dph2.

Family of mitochondrial carrier homologs (MTCH1, MTCH2 and their metazoan orthologs, including Drosophila Mtch), integral proteins of the mitochondrial outer membrane built on a diverged SLC25 solute-carrier fold. PANTHER keeps this family separate from the canonical metabolite-transporting mitochondrial carrier families, which is biologically correct: no member has demonstrated transport activity, and the family as a whole has been co-opted away from the carrier function. Human MTCH2 (and MTCH1) were established in 2022 as the insertases for alpha-helical mitochondrial outer membrane proteins (signal-anchored, tail-anchored, and multi-pass substrates; not beta-barrels), the metazoan functional analog of the yeast MIM complex despite no sequence homology to Mim1/Mim2. Secondary, likely downstream, roles include acting as an OMM receptor for truncated BID in apoptosis (best characterized for mouse Mtch2 and human MTCH1), and regulation of mitochondrial fusion, lipid homeostasis, and stem-cell state transitions reported in mouse Mtch2 models. Current PAINT curation (July-August 2026 IBDs) asserts the insertase trio (GO:0005741, GO:0032977, GO:0045040) at ancestral node PTN000845785 and positive regulation of apoptosis at PTN001324730; the cached human GOA slice predates those IBDs, so human MTCH2 does not yet show the insertase IBAs and still carries older, more generic IBAs (mitochondrion, membrane) from a prior PAINT iteration that the current snapshot has superseded.

Eukaryotic SP-RING (Siz/PIAS RING, also called MIZ-type zinc finger) proteins. The SP-RING is a RING-related domain that binds the SUMO E2 Ubc9/UBE2I and, like a RING E3, activates the E2~SUMO thioester for transfer to a substrate lysine; it has no catalytic cysteine and forms no E3~SUMO intermediate. Most members also carry an N-terminal SAP DNA-binding motif and a PINIT domain. The founding members, budding yeast Siz1 and Siz2, are E3-like factors that together account for most SUMO conjugation in yeast (septins at the bud neck in G2/M, PCNA during S phase). Fission yeast Pli1, Arabidopsis and rice SIZ1/SIZ2, C. elegans GEI-17, Drosophila Su(var)2-10 and vertebrate PIAS1-4 are SUMO E3 ligases for many nuclear substrates. Arabidopsis PIAL1 and PIAL2 are SP-RING ligases specialised for SUMO chain formation ("E4" activity). Vertebrate ZMIZ1 and ZMIZ2 and their invertebrate orthologs (Drosophila tonalli, C. elegans miz-1) form a separate bilaterian clade of transcriptional coregulators. They keep an intact SP-RING zinc site, but direct SUMO ligase activity has not been firmly shown. In vertebrates and flies the PIAS proteins also bind activated STAT dimers and block STAT DNA binding, a coregulator activity that often does not need the SP-RING. Plants, fungi and protists have no STAT-PIAS relationship of this kind.

GT20 glycosyltransferases and their phosphatase-domain relatives make trehalose. Catalytic class I TPS (S. cerevisiae TPS1, S. pombe tps1, SF106) makes trehalose 6-phosphate from UDP-glucose and glucose 6-phosphate. TPS2 and S. pombe tpp1 (SF123, SF121) dephosphorylate it. The regulatory subunits TPS3 and TSL1 (SF15) scaffold the fungal trehalose synthase complex. Plant class II TPS paralogs (TPS5-11) are largely non-catalytic.

Myotubularins include phosphoinositide phosphatases and inactive partners such as MTMR9 and MTMR12. Inactive homologs can stabilize and regulate active partners while lacking the intrinsic catalytic reaction.

VAP proteins provide membrane-associated docking surfaces for lipid-transfer and other trafficking proteins. Canonical VAPA/VAPB and yeast Scs proteins use an MSP domain to recognize FFAT-containing partners, helping organize membrane contacts rather than transporting lipids through an intrinsic catalytic site.

A eukaryote-wide family of Golgi/ER beta1,3-glycosyltransferases with a GT31-type fold. The animal part has two clades. The Fringe clade (Drosophila Fringe; vertebrate Lunatic, Manic and Radical fringe) comprises O-fucosylpeptide beta1,3-N-acetylglucosaminyltransferases that add GlcNAc to O-fucose on Notch EGF repeats; this elongation changes Notch sensitivity to different ligands, typically enhancing Delta responsiveness and reducing Serrate/Jagged responsiveness, and underlies boundary formation and somite segmentation. The sister B3GLCT clade (human B3GLCT, C. elegans ZC250.2, Drosophila CG9109, zebrafish b3galtla) comprises ER beta1,3-glucosyltransferases that add glucose, not GlcNAc, to O-fucose on thrombospondin type 1 repeats; human B3GLCT deficiency causes Peters-plus syndrome. A large plant clade (DUF604 proteins) makes up most of the family and is functionally uncharacterised. C. elegans has no Fringe ortholog.

FAD-dependent squalene monooxygenases epoxidize squalene to 2,3-oxidosqualene, the second committed step of sterol synthesis. They are ER membrane enzymes and the target of allylamine antifungals. The family contains S. cerevisiae ERG1, S. pombe erg1, human SQLE and the plant squalene epoxidases, which form several paralog subfamilies.

NAD-dependent phosphorylating GAPDHs oxidize glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate, the sixth step of glycolysis and its reverse in gluconeogenesis. The family contains bacterial Gap, S. cerevisiae TDH1-3, S. pombe tdh1 and gpd3, plant cytosolic GapC, and animal GAPDH and testis-specific GAPDHS. Animal GAPDH also has moonlighting roles (S-nitrosylation, RNA binding).

Small iron-sulfur proteins with two tandem 4Fe-4S ferredoxin-type domains (Pfam Fer4_7), each binding one [4Fe-4S] cluster. The dominant members are the TYKY / 23-kDa subunit of respiratory complex I: bacterial NuoI, Thermus Nqo9 and mitochondrial NDUFS8. In these the two clusters (N6a and N6b) form the segment of the intramolecular electron wire that bridges cluster N5 and the terminal cluster N2, which reduces quinone. A minority of members are the homologous subunits of complex-I-related hydrogenase and dehydrogenase complexes, such as E. coli formate hydrogenlyase subunit 6 (HycF), hydrogenase-4 component H (HyfH) and F420H2 dehydrogenase subunit I. They are also two-cluster electron-relay proteins, but their complexes oxidise formate or F420H2 rather than NADH. Electron transfer through bound [4Fe-4S] clusters is therefore the family-wide function, while NADH:ubiquinone oxidoreduction and complex I membership belong to the complex I clade only.

FMN-dependent oxidases that convert pyridoxine 5'-phosphate and pyridoxamine 5'-phosphate to pyridoxal 5'-phosphate, the last step of de novo PLP synthesis in E. coli-type bacteria and of B6 salvage in eukaryotes. The family contains bacterial PdxH, S. cerevisiae PDX3, S. pombe SPAC1093.02 and human PNPO; plant PPOX2 forms a separate subfamily.

Deoxyribonuclease II (DNase II) enzymes are acid endonucleases with a phospholipase D-like catalytic fold. They cleave double-stranded DNA at low pH without divalent cations and leave 3'-phosphate ends. They are secreted into the endolysosomal system, where they degrade DNA arriving by phagocytosis, endocytosis or autophagy. The family is eukaryotic. It is present in metazoans, Dictyostelium, ciliates, Trichomonas, heterokonts and some green algae, and is absent from plants and fungi. A small group of Burkholderia sequences most likely came from a eukaryote by horizontal transfer. The best-studied members are vertebrate DNase II-alpha (DNASE2), which digests the DNA of engulfed apoptotic cells and expelled erythroblast nuclei in macrophage phagolysosomes; vertebrate DNase II-beta (DNASE2B, also called DLAD); and the C. elegans paralogs NUC-1, CRN-6 and CRN-7, of which NUC-1 is the main acid DNase and completes the degradation of apoptotic-cell DNA. Divergent uses include the toxin plancitoxin-1 of the crown-of-thorns starfish. Dictyostelium carries a lineage-specific expansion of uncharacterized paralogs (subfamilies SF22 and SF25).

This dolichol-phosphate glycosyltransferase family contains enzymes producing different lipid-linked sugar donors. ALG5 transfers glucose from UDP-glucose to dolichyl phosphate, whereas DPM-type enzymes generate dolichyl-phosphate mannose. Both feed glycosylation pathways but the sugar donor and product are different.

uS13-related proteins contribute to the structure and function of the small ribosomal subunit. The family includes bacterial-type and mitochondrial uS13 proteins as well as eukaryotic cytosolic counterparts. The mitochondrial small-subunit protein Sws2 therefore shares a ribosomal function without sharing the localization of every family member.

Dph5 is the S-adenosyl-L-methionine-dependent methyltransferase of the second step of diphthamide biosynthesis. It acts on the 3-amino-3-carboxypropyl (ACP) histidine that the Dph1-Dph2 (archaeal Dph2) radical-SAM-like step installs on translation elongation factor 2, and it shares the tetrapyrrole (uroporphyrinogen III) methylase fold with cobalamin-pathway methylases. The reaction differs between the two domains of life that make diphthamide. Archaeal Dph5 trimethylates the amino group of the ACP side chain (diphthine synthase, GO:0004164, which GO restricts to Archaea). Yeast Dph5 additionally methylates the carboxylate and produces diphthine methyl ester (GO:0141133, restricted by GO to Eukaryota), which the WD40 methylesterase Dph7 then hydrolyses before Dph6 amidates the free carboxylate. Archaea have no Dph7. Diphthamide occurs only on archaeal and eukaryotic EF2, yet the family also contains a small number of bacterial tetrapyrrole-methylase-domain proteins.

Type 1 IPP isomerases interconvert isopentenyl diphosphate and dimethylallyl diphosphate, the two C5 units of isoprenoid synthesis. The family contains S. cerevisiae IDI1, S. pombe idi1, human IDI1 and IDI2, and plant IPI isozymes.

Six-bladed beta-propeller, metal-dependent hydrolases of the SMP-30/gluconolactonase/LRE family. Vertebrate regucalcin (SMP-30) is the gluconolactonase of L-ascorbate biosynthesis in mammals that make vitamin C and has additional proposed roles in calcium signalling. Characterized bacterial and archaeal members are sugar-acid lactonases of pentose and sulfosugar catabolism: Caulobacter XylC (D-xylonolactone), Azospirillum AraB (L-arabinolactone), Haloferax XacC (pentonolactones) and the Pseudomonas putida SQ1 6-deoxy-6-sulfogluconolactonase of the sulfo-ED pathway. Yeast, Candida, archaeal and Bacillus members in the inventory are uncharacterized or only putative lactonases. The 21 SwissProt inventory members fall into SF47 (12: microbial lactonases plus fish and frog regucalcins) and SF54 (9: mammalian and avian regucalcins).

GNAT acetyltransferases related to serotonin N-acetyltransferase. Vertebrate AANAT acetylates serotonin in the rate-limiting, circadian step of melatonin synthesis. S. cerevisiae PAA1 acetylates polyamines (putrescine, spermidine) and aralkylamines.

FAD-dependent peroxisomal acyl-CoA oxidases catalyse the first, H2O2-producing step of peroxisomal beta-oxidation. Substrate preference differs by paralog: ACOX1 for straight-chain and very-long-chain acyl-CoAs, ACOX2 for the bile-acid intermediate trihydroxycholestanoyl-CoA, ACOX3 for pristanoyl-CoA, and S. cerevisiae POX1, the single fungal enzyme.

This domain-rich family contains extracellular proteins with distinct inhibitory and signaling roles. Kazal-containing protease inhibitors coexist in the classification with follistatin-related proteins and larger extracellular organizers. A shared cysteine-rich domain does not identify either the inhibited protease or the growth-factor ligand.

FtsJ/RlmE-related methyltransferases modify ribose groups in RNA. The family includes bacterial ribosomal RNA enzymes, mitochondrial Mrm2 and eukaryotic enzymes acting on tRNA or preribosomal RNA. RNA type, modified nucleotide and subcellular location define the important functional boundaries. Human MRM2 also has a ribosome-assembly function that does not require its methyltransferase activity, and disrupting its fly ortholog causes mitochondrial developmental defects.

Eukaryote-wide family of small coiled-coil proteins (about 190-350 residues) typified by Aspergillus nidulans NudE, the first member found, as a multicopy suppressor of the LIS1-homolog mutant nudF. Every characterized member binds LIS1 (NudF/Pac1/LIS-1) through an N-terminal coiled coil and works with it to regulate cytoplasmic dynein. In vitro and in cells, NudE proteins tether LIS1 to dynein, help dynein reach microtubule plus ends, and promote the LIS1-dependent high-force, activated dynein state. The conserved biological output is dynein-driven nuclear migration along microtubules (hyphal nuclear distribution in filamentous fungi, spindle/nuclear positioning in budding yeast, nuclear migration in C. elegans hypodermal and P-cell precursors, nucleokinesis in migrating mammalian neurons) and dynein-driven retrograde organelle and endosome transport. Vertebrates carry two paralogs, NDE1 (SF2) and NDEL1 (SF0), which have gained a C-terminal region that binds CENP-F and other partners. That region targets them to kinetochores, the nuclear envelope and centrosomes in mitosis and neurodevelopment. Kinetochore targeting via CENP-F-like proteins is shared with fly NudE and worm NUD-2, but has not been shown for any fungal member. Centrosome residence and effects on centrosomal microtubule nucleation are documented only for the vertebrate paralogs. The family therefore has one conserved molecular role (the LIS1-dynein regulatory coiled coil) with metazoan and vertebrate additions that the deep PAINT node does not distinguish.

GFAT enzymes couple glutamine hydrolysis to conversion of fructose-6-phosphate into glucosamine-6-phosphate, supplying the hexosamine biosynthetic pathway. Related sugar-isomerase domains also occur in glucosamine deamination and other reactions, so a broad structural grouping extends beyond the complete two-domain GFAT reaction.

PTHR10953 contains the E1-like enzymes that adenylate the C-terminal glycine of a ubiquitin-fold protein. The bacterial members include MoeB, which activates the MoaD sulfur carrier of molybdopterin synthase, ThiF, which activates ThiS in thiamine biosynthesis, and rhodanese-domain MoeZ-type proteins. The eukaryotic members include MOCS3/UBA4 and the ubiquitin, SUMO, NEDD8, UFM1, ATG7 and ATG12 activating enzymes. The shared chemistry is ATP-dependent adenylation of a carrier C terminus; the carrier, the downstream thioester or thiocarboxylate chemistry and the biological process differ between subfamilies.

Single-chain FAD-dependent amine oxidases of the D-amino acid oxidase (DAO) fold that oxidatively demethylate or oxidise secondary-amine amino acids with O2 as acceptor. The family contains bacterial monomeric sarcosine oxidase (MSOX, e.g. Arthrobacter sp. TE1826 SoxA, Bacillus MSOX) and enterobacterial N-methyl-L-tryptophan oxidase (SolA/MTOX) in subfamily SF7, animal peroxisomal sarcosine/L-pipecolate oxidase (PIPOX) and fungal pipecolate oxidase in SF46, fungal fructosyl amino acid oxidases in SF24 and fission-yeast L-saccharopine oxidase in SF26. The shared chemistry is FAD-dependent oxidation of a CH-NH bond with oxygen as acceptor; the substrate (sarcosine, N-methyl-L-tryptophan, L-pipecolate, fructosyl amino acids, saccharopine) is subfamily-specific.

GHMP-superfamily enzymes that ATP-dependently decarboxylate mevalonate 5-diphosphate to isopentenyl diphosphate, the last step of the mevalonate pathway (S. cerevisiae MVD1/ERG19, S. pombe mvd1, human MVD).

SdhC/SDHC is one of the two integral membrane subunits of complex II. With SdhD/SDHD it anchors the flavoprotein and iron-sulphur subunits to the membrane, binds heme b and forms the ubiquinone-binding site. The family contains bacterial SdhC, S. cerevisiae SDH3, S. pombe sdh3 and human SDHC.

HES/HEY-related bHLH proteins regulate developmental transcription through partner-dependent dimerization, DNA recognition and corepressor interactions. Direct zebrafish experiments show that Her7:Hes6 heterodimers bind cyclic-gene promoters strongly whereas Hes6 homodimers do not. Developmental process, DNA-binding competence and repressive output vary among family members and dimer combinations.

Importin/exportin relatives are soluble transport receptors that carry selected proteins through the nuclear pore. Importin-7/Moleskin belongs to an import-receptor branch, while other members of this family include importin-8/9/11 and exportin-2. Cargo recognition and transport direction are central functional distinctions.

This family groups insect CHK/ecdysteroid-kinase-like proteins. The kinase-like architecture raises a specific hypothesis of small-molecule phosphorylation, including ecdysteroid phosphorylation, rather than automatically implying phosphorylation of proteins. Individual members remain unevenly characterized.

SmF/Lsm6 proteins are related small subunits of RNA-associated rings. SmF belongs to canonical spliceosomal Sm particles; Lsm6 is shared by the nuclear U6-associated Lsm2-8 ring and the cytoplasmic Lsm1-7 mRNA-decapping ring. Complex identity therefore changes the biological process assigned to a member.

The peptidoglycan recognition proteins (PGRPs) share the bacteriophage T7 lysozyme amidase-2 fold, which binds bacterial peptidoglycan. The fold is catalytic in its ancestral form: members that retain a zinc site are N-acetylmuramoyl-L-alanine amidases (EC 3.5.1.28) that hydrolyse the lactyl-amide bond linking the glycan backbone to the stem peptide, scavenging immunostimulatory peptidoglycan fragments. A large part of the family has lost the zinc site and repurposed the same binding surface for pattern recognition: these members are receptors that bind peptidoglycan and signal, notably the Drosophila and mosquito PGRP-LC and PGRP-LE receptors that activate the IMD pathway. Catalytic and non-catalytic members therefore share a fold, a ligand, and a name, while differing in whether they turn the ligand over.

NDRG-family proteins are alpha/beta-hydrolase-fold interaction proteins with diverse regulatory roles. Human and mouse NDRG2 structures support a nonenzymatic scaffold rather than a conventional hydrolase; the shared fold does not specify a conserved enzymatic substrate or signaling pathway.

ER membrane 3-hydroxyacyl-CoA dehydratases catalyse the third step of each fatty-acid elongation cycle, dehydrating very-long-chain (3R)-3-hydroxyacyl-CoA to trans-2-enoyl-CoA. The family contains S. cerevisiae PHS1, S. pombe phs1, Arabidopsis PAS2 and human HACD1-4.

This kinase family combines cell-cycle inhibitory kinases with stress-responsive translation-control kinases and other related enzymes. WEE1-family proteins inhibit CDK-driven mitotic entry, whereas eIF2-alpha kinases control translation during specific stresses. Shared protein-kinase chemistry does not imply common substrates or phosphoacceptor specificity.

Intramembrane UbiA-superfamily prenyltransferases. The main subfamily (SF28) attaches the polyprenyl tail to 4-hydroxybenzoate, the first committed step of ubiquinone synthesis: bacterial UbiA, S. cerevisiae COQ2, S. pombe ppt1 and human COQ2 in the mitochondrial inner membrane. Smaller subfamilies prenylate fungal meroterpenoid precursors (AusN/AndD, SF39) or make decaprenyl-phosphoribose (SF5).

GH65 enzymes act on alpha-glucosides. The family contains fungal acid trehalases (S. cerevisiae ATH1, vacuolar), animal protein-glucosylgalactosylhydroxylysine glucosidase (PGGHG; both in SF8), bacterial maltose and trehalose phosphorylases (SF14), and mycobacterial glycosyltransferases (SF13).

6-Phosphogluconolactonases hydrolyse 6-phospho-D-glucono-1,5-lactone to 6-phosphogluconate, the second step of the oxidative pentose phosphate pathway. The family contains bacterial Pgl, S. cerevisiae SOL3/SOL4, S. pombe SPCC16C4.10, human PGLS, and plant cytosolic and plastid PGL isozymes.

Family built around adenylylsulfate (APS) kinase, which phosphorylates adenosine 5'-phosphosulfate to 3'-phosphoadenosine 5'-phosphosulfate (PAPS). It contains three architectures. (1) Monofunctional APS kinases of about 200-300 residues: bacterial CysC (E. coli, Bacillus), fungal MET14 (S. cerevisiae, S. pombe) and the plant APK1-4 isoforms. (2) Animal bifunctional PAPS synthases (human PAPSS1 and PAPSS2, worm pps-1) with an N-terminal APS kinase domain fused to a C-terminal ATP sulfurylase domain, which make PAPS from sulfate in two steps. (3) The Arabidopsis plastid ATP sulfurylases APS1-4 (about 465 residues), which carry only the ATP sulfurylase and PUA-like domains and no APS kinase domain; PANTHER places them here through their similarity to the sulfurylase half of PAPSS. Members act in sulfate activation, either for reductive assimilation (fungi, bacteria, plants) or for sulfonation (animal PAPS).

Nonheme Fe(II)-dependent ring-cleaving dioxygenases of the cupin (RmlC-like jelly-roll) superfamily that open the aromatic ring of homogentisate to give 4-maleylacetoacetate, the third step of the homogentisate central pathway of L-phenylalanine and L-tyrosine degradation to fumarate and acetoacetate. Members include human HGD (alkaptonuria gene), mouse Hgd, Arabidopsis HGO, Aspergillus HmgA and bacterial HmgA such as Pseudomonas putida KT2440 Q88E47, whose crystal structures trapped the substrate, superoxo, alkylperoxo and product intermediates. The active site iron is held by two histidines and a glutamate (human His335, Glu341, His371; P. putida His331, Glu337, His367), and the enzymes assemble as hexamers (dimers of trimers).

Small membrane subunit family of the proton-pumping NADH:quinone oxidoreductases: bacterial NuoA, mitochondrial ND3, and the plastid-encoded NdhC of the chloroplast NDH complex. Bacterial and mitochondrial members are respiratory, reducing ubiquinone in NDH-1 or respiratory complex I. The plastid NdhC clade belongs to the thylakoid NAD(P)H dehydrogenase complex (GO:0010598), which runs photosynthetic cyclic electron flow around photosystem I and chlororespiration and reduces plastoquinone. The compartment-neutral complex term (NADH dehydrogenase complex) is true family-wide; the ubiquinone-specific activity term is not.

CAZy family GT47 glycosyltransferases. In the PAINT snapshot used here the family includes the animal exostosins (EXT1, EXT2, EXTL3 and fly/worm orthologs), which polymerise heparan sulfate on proteoglycan core proteins. Current UniProt records place human EXT1 in PTHR48261, but invertebrate exostosins remain in the family (C. elegans rib-1, O01704, in SF129 "EXOSTOSIN-1"), so the family still spans animal heparan sulfate polymerases and plant cell-wall enzymes. The plant members act on different wall polysaccharides: the IRX10/XYS1 clade (beta-1,4-xylan synthases), IRX7/FRA8 (xylan reducing-end sequence), MUR3 and related GT11-GT20 proteins (xyloglucan galactosyltransferases), ARAD1/ARAD2 (pectic arabinan arabinosyltransferases) and XGD1 (xylogalacturonan xylosyltransferase). This review covers the IRX10/XYS1 clade and the PAINT nodes that place xylan terms; the other nodes are not assessed.

Gamma-glutamyl phosphate reductases reduce L-glutamyl 5-phosphate to glutamate 5-semialdehyde, the second step of proline synthesis from glutamate. In bacteria and fungi this is a separate enzyme (ProA, S. cerevisiae PRO2, S. pombe pro1). In animals (ALDH18A1) and plants (P5CS) it is the C-terminal domain of a bifunctional P5C synthase whose N-terminal domain is glutamate 5-kinase.

PTHR11070 groups superfamily 1A DNA helicases that translocate 3'-to-5' on single-stranded DNA and unwind duplex DNA with ATP hydrolysis. Members are found across bacteria and eukaryotes and have diverse roles. The bacterial helicases UvrD, PcrA and Rep work in excision repair, mismatch repair, replication and anti-recombination. RecB is the motor-nuclease subunit of RecBCD, and AddA is the motor-nuclease subunit of AddAB. HelD and HelR are RNA polymerase recycling motors. Eukaryotic Srs2 and FBH1 regulate Rad51 nucleoprotein filaments. The 3'-to-5' helicase motor is the common element. Nuclease activity, complex membership and particular repair pathways belong to individual subfamilies. RecB (PTHR11070:SF23) carries a C-terminal PD-(D/E)XK nuclease domain and is the only nuclease subunit of the RecBCD (exodeoxyribonuclease V) complex.

Zinc-dependent deaminases of the CDA fold. The family contains fungal cytosine deaminases (S. cerevisiae FCY1, Candida FCA1), bacterial TadA and eukaryotic TAD2/ADAT2 tRNA adenosine-34 deaminases, the inactive TAD3/ADAT3 partner subunits, guanine deaminase GuaD, and the deaminase domain of riboflavin biosynthesis RibD/PyrD.

Isochorismatase-fold amidases that hydrolyse nicotinamide to nicotinate in NAD salvage (bacterial PncA, S. cerevisiae PNC1, S. pombe pnc1). Mycobacterial PncA also activates the prodrug pyrazinamide.

Sirtuins couple NAD consumption to removal of acyl groups from protein lysines, with substantial variation in acyl-group preference and cellular substrate selection. SIRT5 is specialized toward negatively charged lysine acylations such as succinylation, malonylation and glutarylation. Nuclear histone regulation and mitochondrial metabolic control are different branch contexts.

Zinc-dependent deoxycytidylate (dCMP) deaminases (DCTD, EC 3.5.4.12) hydrolytically deaminate dCMP to dUMP and ammonia, supplying the thymidylate synthase substrate in Gram-positive bacteria, eukaryotes and T-even phages. They are homohexamers. Each protomer has one cytidine/dCMP deaminase-like domain with a catalytic site and an allosteric site, at which dCTP activates and dTTP inhibits. Budding-yeast DCD1 is the dCMP deaminase of S. cerevisiae, which has no dCTP deaminase. Vertebrates also have a paralog, CDADC1 (NYD-SP15). It carries two DCTD-like domains, of which only the C-terminal one is active, and it is a dCTP deaminase that converts dCTP directly to dUTP. CDADC1 has little or no dCMP deaminase activity.

Nicotinate phosphoribosyltransferases make nicotinate mononucleotide from nicotinate and PRPP, coupled to ATP hydrolysis, in the Preiss-Handler NAD salvage route. The family contains bacterial PncB, S. cerevisiae NPT1, S. pombe SPAC1486.06 and human NAPRT.

Vps35 proteins form the elongated alpha-solenoid central scaffold of the heterotrimeric retromer cargo-selective complex (Vps35-Vps26-Vps29) across eukaryotes. Vps35 binds Vps26 at its N-terminal arrestin-interacting end and Vps29 at its C-terminal horseshoe-shaped arch, recognizes cytoplasmic sorting motifs on endosomal transmembrane cargo proteins, and recruits accessory trafficking machinery such as the WASH complex and TBC1D5 to mediate endosome-to-trans-Golgi network retrograde retrieval and endosome-to-plasma membrane recycling.

PTHR11102 groups proteins built from Sel1-like repeats (SLRs), helix-turn-helix units related to tetratricopeptide repeats that form solenoid scaffolds for protein-protein and protein-ligand interactions. In eukaryotes, SEL1L, nematode SEL-1 and yeast Hrd3 are endoplasmic-reticulum membrane adaptors of the HRD1 ubiquitin-ligase complex in ER-associated degradation (ERAD). Most members are bacterial and are unrelated to ERAD. Pseudomonas and Azotobacter AlgK is an outer-membrane lipoprotein scaffold of the alginate secretion machinery that binds AlgX, alginate and the AlgE context. Rhizobial ExoR regulates exopolysaccharide production, Caulobacter PodJ is a polar localization factor, Vibrio MotX is a sodium-flagellar component and E. coli EsiB binds secretory IgA. The repeat scaffold is the only property shared family-wide; the process each scaffold serves is lineage-specific.

Ferrochelatases insert Fe2+ into protoporphyrin IX to make protoheme, the last step of heme synthesis. The eukaryotic enzymes sit on the matrix side of the mitochondrial inner membrane, and the animal ones carry a [2Fe-2S] cluster. The family contains bacterial HemH, S. cerevisiae HEM15, S. pombe hem15, human FECH and plant FC1/FC2.

GTP cyclohydrolase I opens the imidazole ring of GTP to make 7,8-dihydroneopterin triphosphate, the first committed step of both folate synthesis (bacteria, fungi, plants) and tetrahydrobiopterin synthesis (animals). The family contains bacterial FolE, S. cerevisiae FOL2, S. pombe SPAC17A5.13 (SF7) and animal GCH1 (SF11).

The alpha subunit of succinyl-CoA synthetase binds CoA and phosphate and carries the phosphohistidine intermediate of the TCA-cycle substrate-level phosphorylation step. It is nucleotide-agnostic: the beta subunit (PTHR11815) binds the nucleotide and sets ADP or GDP specificity. PANTHER roots the family at LUCA (PTN000122012), with archaeal and bacterial SucD and a single eukaryotic clade (PTN000122014) that branches from within the bacterial sequences as sister to the proteobacterial clade, consistent with a mitochondrial origin. Most eukaryotes have one alpha gene (S. cerevisiae LSC1, S. pombe SPAC16E8.17c, human SUCLG1); plants have two. Because one alpha subunit serves whichever beta subunits a genome encodes, every nucleotide-specific term on this family depends on the beta-subunit repertoire of the lineage, which the alpha tree itself cannot show. The family also contains E. coli FdrA/YahF and AllF, and the alpha subunits of malate-CoA ligase and sulfoacetate-CoA ligase, which are not succinyl-CoA synthetase subunits.

Calcineurin-like metallophosphoesterase-fold family spanning two deeply divergent evolutionary branches: (1) prokaryotic and archaeal catalytically active metallophosphodiesterases such as Escherichia coli YfcE, Bacillus subtilis YsnB, and Methanocaldococcus jannaschii MJ0623 (PANTHER:PTHR11124:SF26), which coordinate a binuclear metal center to hydrolyze phosphodiester bonds; and (2) eukaryotic Vps29 proteins (PANTHER:PTHR11124:SF12), which evolved into catalytically inactive structural scaffolds that bind the C-terminal alpha-solenoid of VPS35 (in the retromer cargo-selective complex) and VPS35L (in the retriever complex) to mediate endosomal cargo retrieval and recruit regulatory factors such as TBC1D5 and ANKRD27/VARP.

ATP-grasp glutathione synthetases ligate glycine to gamma-glutamylcysteine, the second step of glutathione synthesis (S. cerevisiae GSH2, S. pombe gsa1, human GSS, plant GSH2). Bacterial GshB is unrelated.

Saccharopine dehydrogenases interconvert saccharopine with lysine or glutamate. In the fungal alpha-aminoadipate pathway of lysine synthesis, saccharopine reductase (S. cerevisiae LYS9, S. pombe lys9) makes saccharopine from aminoadipate semialdehyde and glutamate, and saccharopine dehydrogenase (LYS1, S. pombe lys3) releases lysine. In animal lysine catabolism the bifunctional AASS runs the reverse: its lysine-ketoglutarate reductase domain makes saccharopine and its saccharopine dehydrogenase domain releases glutamate.

Beta-adaptin large subunits (IPR026739) of eukaryotic heterotetrameric adaptor protein complexes (AP-1, AP-2, AP-3, and AP-4). Each beta subunit contains an N-terminal alpha-solenoid trunk domain that heterodimerizes with the complex-specific large subunit (gamma in AP-1, alpha in AP-2, delta in AP-3, epsilon in AP-4), a flexible hinge region (which carries a canonical clathrin-box motif in AP-1, AP-2, and AP-3 beta subunits), and a C-terminal appendage domain. The beta-adaptin fold identifies a cargo-adaptor trafficking component without fixing a single organelle or vesicle coat across all four complexes.

Mur-ligase-fold enzymes that add glutamate to pteroates. Dihydrofolate synthase adds the first glutamate to dihydropteroate (S. cerevisiae FOL3, S. pombe fol3; SF0). Folylpolyglutamate synthase extends the polyglutamate tail of folates (S. cerevisiae MET7, S. pombe met7, animal FPGS; SF5). Bacterial FolC carries out both reactions.

ER membrane 3-ketoacyl-CoA synthases catalyse the condensation step of each fatty-acid elongation cycle. Paralogs differ in chain-length and saturation preference: S. cerevisiae ELO1 (C14 to C16), ELO2 (up to C24) and ELO3 (C26 for sphingolipids); S. pombe elo1/elo2; and mammalian ELOVL1-7, which cover saturated, monounsaturated and polyunsaturated acyl-CoAs.

Glutamate-cysteine ligases make gamma-glutamylcysteine, the first and rate-limiting step of glutathione synthesis. Animal GCLC is regulated by the modifier subunit GCLM. The family contains S. cerevisiae GSH1, S. pombe gcs1 and human GCLC.

GT8 retaining glycosyltransferases. Glycogenins (S. cerevisiae GLG1/GLG2, human GYG1/GYG2) auto-glucosylate a tyrosine to prime glycogen synthesis. The family also contains plant galactinol synthases, plant GUX xylan glucuronosyltransferases, S. cerevisiae GNT1 (Golgi N-acetylglucosaminyltransferase) and uncharacterized S. pombe members.

Inositol 5-phosphatases remove the phosphate at the 5 position of soluble inositol phosphates or membrane phosphoinositides. Synaptojanins combine this activity with an additional Sac1-like phosphatase region and regulatory domains. Different family architectures target distinct lipid pools and cellular trafficking events.

KH-domain RNA-binding proteins in this family regulate RNA maturation and expression. SF1/branchpoint-binding proteins recognize intronic branchpoint regions during early spliceosome assembly, whereas STAR/QKI/KHDRBS-related proteins regulate selected RNA targets through alternative splicing and other post-transcriptional mechanisms.

Exportins mediate nuclear export of distinct cargo classes. Exportin-1 recognizes protein export signals, whereas exportin-5 and related receptors export structured RNAs and selected other cargos.

Mg2+-dependent chorismate-utilizing enzymes that aminate or isomerize chorismate. Subfamilies specialize: anthranilate synthase component I (TrpE; S. cerevisiae TRP2, S. pombe trp3) for tryptophan; aminodeoxychorismate synthase (PabB; the fused fungal ABZ1, S. pombe abz1) for folate; and isochorismate synthase (MenF/EntC) for menaquinone and siderophores.

Carboxylate-bridged di-iron hydroxylases that hydroxylate C5 (C6 in some numbering) of demethoxyubiquinone, the penultimate step of ubiquinone synthesis, on the matrix face of the mitochondrial inner membrane. The family contains bacterial Coq7, S. cerevisiae CAT5/COQ7, S. pombe coq7, C. elegans CLK-1 and human COQ7.

Trimeric dUTP pyrophosphatases (dUTPase, EC 3.6.1.23) are Mg2+-dependent hydrolases that cleave dUTP to dUMP and diphosphate. The reaction does two things. It keeps the dUTP/dTTP ratio low so that DNA polymerases do not incorporate uracil, and it supplies dUMP, the substrate of thymidylate synthase. The enzyme is essential in yeast and E. coli, and is found in bacteria, eukaryotes and many DNA viruses and prophages. Human DUT is expressed from one gene as a nuclear (DUT-N) and a mitochondrial (DUT-M) isoform. The family also contains a small number of dUTPase-like sequences that PANTHER labels as inactive or as domain-only proteins.

Polynucleotide phosphorylases are homotrimeric, ring-shaped 3'-to-5' exoribonucleases with two RNase PH domains per protomer plus KH and S1 RNA-binding domains. They degrade single-stranded RNA processively by phosphorolysis, releasing nucleoside diphosphates, and can polymerize NDPs. Bacterial PNPases act in the cytoplasm, often bound to the RNase E degradosome scaffold; eukaryotic members (PNPT1) are imported into mitochondria (and plastids in plants), where they degrade mitochondrial mRNA and process RNA 3' ends.

Zinc-dependent amidohydrolases that deaminate guanine to xanthine in purine catabolism (bacterial GuaD, S. cerevisiae GUD1, S. pombe SPCC1672.03c, human GDA). A small subfamily (SF48) contains HutF formimidoylglutamate deiminases of histidine utilization.

Eumetazoan family of membrane-anchored receptor ligands that bind and activate Eph receptor tyrosine kinases across cell-cell contacts. Members share an extracellular cupredoxin-like Eph receptor-binding domain (RBD) and fall into two structural subclasses in vertebrates: glycosylphosphatidylinositol (GPI)-anchored ephrin-A ligands (EFNA1-EFNA5, preferentially engaging EphA receptors) and single-pass type I transmembrane ephrin-B ligands (EFNB1-EFNB3, preferentially engaging EphB receptors and capable of reverse intracellular signaling via their conserved cytoplasmic tail and PDZ-binding motif), alongside invertebrate ephrins such as Drosophila Ephrin and Caenorhabditis elegans EFN-1 to EFN-4.

PTHR11309 groups the class-F (Frizzled) seven-transmembrane receptors together with two sets of relatives that no longer do what the family name implies. The core of the family is the Frizzled Wnt receptors, which bind lipidated Wnt ligands through an extracellular cysteine-rich domain and signal through Dishevelled into the canonical beta-catenin branch and the beta-catenin-independent branches. Smoothened sits inside the same family by sequence and fold but is not a Wnt receptor at all: it is the obligate transducer of Hedgehog signaling, activated by sterols occupying its cysteine-rich domain and an intramolecular channel through its transmembrane core, and it engages Patched rather than Wnt. The secreted Frizzled-related proteins retain only the cysteine-rich domain, have no transmembrane segment, and act extracellularly as ligand-binding modulators rather than as receptors. The family is therefore a textbook case of one ancestral receptor role kept by one branch and abandoned by two others, and PANTHER's own PAINT annotations record the abandonment explicitly as inferred losses rather than leaving it to be discovered downstream.

Cyclic-nucleotide phosphodiesterases terminate or shape second-messenger signals by hydrolyzing cyclic nucleotides. Members differ in cAMP versus cGMP preference, dual specificity and regulatory domains. PDE4/Dunce-type enzymes belong to a cAMP-directed branch, distinct from retinal cGMP phosphodiesterases.

Nucleoside diphosphate kinases redistribute terminal phosphate among nucleotide pools through a phosphohistidine intermediate. The Awd/NM23-type catalytic role contributes to nucleotide homeostasis, while individual proteins can also participate in trafficking and developmental regulation. Those cellular roles need not imply a different phosphotransfer reaction.

ER membrane di-iron acyl-CoA desaturases. The stearoyl-CoA delta-9 desaturases (S. cerevisiae OLE1, S. pombe ole1, animal SCD1-5) insert the first cis double bond into palmitoyl- and stearoyl-CoA. Other subfamilies include plant and insect desaturases with different regiospecificity (delta-12 and others) and bacterial homologs.

Binuclear manganese ureohydrolases that hydrolyse guanidino or formimino groups. Substrates overlap across some subfamilies: the plant ARGAH enzymes include dual arginase/agmatinase activities, whereas other branches specialize in agmatine, guanidino acids, N1-aminopropylagmatine or formiminoglutamate hydrolysis. Consequently, neither an arginase name nor membership in the base family alone determines substrate specificity.

AMP deaminases hydrolytically deaminate AMP to IMP, part of the purine nucleotide cycle and of adenylate pool control. The family contains S. cerevisiae AMD1, plant FAC1/AMPD and human AMPD1-3, and an inactive S. cerevisiae paralog, YBR284W (SF7).

ATP-dependent 5-oxoprolinases open 5-oxoproline (pyroglutamate) to glutamate, closing the gamma-glutamyl cycle (S. cerevisiae OXP1, S. pombe oxp1 and oxp2, human OPLAH). Bacterial hydantoinase/oxoprolinase-related proteins (SF23) form a separate subfamily.

ABCD half-transporters. ABCD1-3 and the S. cerevisiae PXA1/PXA2 heterodimer move fatty acyl-CoAs (very-long-chain, branched-chain and bile-acid intermediates) into peroxisomes for beta-oxidation. ABCD4 is a lysosomal cobalamin exporter that works with LMBD1.

Mn- and Fe-containing superoxide dismutases dismutate superoxide in the mitochondrial matrix (eukaryotic SOD2) or cytosol (bacterial SodA/SodB). The family contains bacterial SodA, S. cerevisiae SOD2, S. pombe sod2, C. elegans sod-2/sod-3, human SOD2 and plant MSD/FSD isozymes.

Carbamoyl-phosphate synthase (CPS) proteins. SF53 holds the CPS large (synthetase) chains: bacterial CarB, the fungal arginine-specific CPSase A large chains (S. cerevisiae CPA2, S. pombe arg4), plant chloroplastic CARB, Bacillus-type pyrimidine-specific PyrAB, split archaeal CarB halves, and vertebrate mitochondrial CPS1. SF4 holds the fungal and plant arginine-specific small (glutamine amidotransferase) chains such as S. cerevisiae CPA1. SF5 holds the CAD-type multifunctional proteins of pyrimidine synthesis (human CAD, yeast URA2, S. pombe ura1), which fuse glutamine amidotransferase, synthetase and aspartate carbamoyltransferase domains.

Phosphoglycerate kinases transfer phosphate from 1,3-bisphosphoglycerate to ADP, the first ATP-generating step of glycolysis, and run in reverse in gluconeogenesis. The family contains bacterial Pgk, S. cerevisiae PGK1, S. pombe pgk1, human PGK1 and testis PGK2, and plant cytosolic and plastid PGKs.

Zinc amidohydrolases of the adenosine deaminase family. Cytosolic ADA deaminates adenosine and 2'-deoxyadenosine to inosine; its loss causes severe combined immunodeficiency. ADA2 (CECR1) is a secreted, growth-factor-like adenosine deaminase. ADAL/MAPDA deaminates N6-methyl-AMP rather than adenosine.

Large secreted plasma and cell-surface glycoproteins sharing the conserved macroglobulin (MG1-MG8), CUB, and alpha-helical thioester-containing domain (TED) architecture (InterPro:IPR001599). Despite a common ancestral fold, the superfamily diverged into two functionally distinct major branches in metazoans: (1) broad-spectrum protease-trapping endopeptidase inhibitors—represented by alpha-2-macroglobulin (A2M), pregnancy zone protein (PZP), alpha-2-macroglobulin-like protein 1 (A2ML1), murinoglobulins, and ovostatins—in which protease cleavage of a permissive bait region triggers conformational collapse around the attacking peptidase; and (2) central complement cascade pro-proteins—complement C3, C4 (C4A/C4B), and C5—which lack protease-trapping activity and are instead cleaved at a specific convertase site to release a small N-terminal four-helix-bundle anaphylatoxin (C3a, C4a, or C5a; InterPro:IPR000020) and a large C-terminal fragment (C3b, C4b, or C5b) that drives opsonization, convertase assembly, or membrane attack complex (MAC, C5b-9) pore formation. Notably, C5 (PANTHER:PTHR11412:SF83) has lost the internal beta-cysteinyl- gamma-glutamyl thioester sequence retained by C3, C4, A2M, and GPI-anchored CD109, specializing instead for C5a anaphylatoxin GPCR signaling (via C5aR1 and C5aR2; GO:0038178) and C5b-nucleated MAC assembly.

Core membrane subunit family of the proton-pumping NADH:quinone oxidoreductases: bacterial NuoH, mitochondrial ND1, and the plastid-encoded NdhA of the chloroplast NDH complex. Bacterial and mitochondrial members are respiratory, oxidizing NADH and reducing ubiquinone in NDH-1 or respiratory complex I during aerobic respiration. The plastid NdhA clade belongs to the thylakoid NAD(P)H dehydrogenase complex (GO:0010598), which runs photosynthetic cyclic electron flow around photosystem I and chlororespiration and reduces plastoquinone. PAINT already scopes the complex-term assertions in this family to taxon-restricted nodes; the remaining family-level assertions of respiratory process and NADH-donor activity still leak into the plastid clade.

Small three-transmembrane-helix membrane subunit of proton-pumping NADH:quinone oxidoreductases: bacterial NuoK, mitochondrially encoded ND4L and the plastid NdhE of the chloroplast NDH complex. In E. coli NDH-1, NuoK forms part of the E-channel proton pathway next to the quinone site with NuoA, NuoJ and NuoH, and its conserved membrane-embedded glutamates are needed to couple electron transfer to proton translocation. Bacterial and mitochondrial members act in respiratory complex I, which reduces ubiquinone (or menaquinone). Plastid NdhE acts in the thylakoid NDH complex, which reduces plastoquinone with ferredoxin as donor. The compartment-neutral term NADH dehydrogenase complex holds family-wide; respiratory chain complex I does not hold for the plastid clade.

Secreted vertebrate opioid and opioid-related neuropeptide polyprotein precursors (InterPro:IPR006024), comprising three paralogous subfamilies: Proenkephalin-A (PENK, PANTHER:PTHR11438:SF3; cleaved into six Met-enkephalin copies, including C-terminally extended heptapeptide/octapeptide forms and BAM8-22, plus one Leu-enkephalin copy), Proenkephalin-B / Prodynorphin (PDYN, PANTHER:PTHR11438:SF4; cleaved into alpha- and beta-neoendorphin, dynorphin A, dynorphin B/rimorphin, leumorphin, and Leu-enkephalin), and Prepronociceptin (PNOC, PANTHER:PTHR11438:SF2; cleaved into the heptadecapeptide nociceptin / orphanin FQ). All three precursors share a conserved N-terminal cysteine-rich domain and tandem dibasic prohormone convertase cleavage sites releasing peptides with the canonical Tyr-Gly-Gly-Phe-Met/Leu (PENK, PDYN) or Phe-Gly-Gly-Phe (PNOC) message motif, which act as endogenous opioid peptide ligands (GO:0001515) for the Gi/o-coupled opioid receptor GPCRs OPRD1, OPRM1, OPRK1, and OPRL1 to initiate the G protein-coupled opioid receptor signaling pathway (GO:0038003) and its canonical adenylate cyclase-inhibiting opioid receptor signaling pathway (GO:0031635).

Alpha/beta-hydrolase-fold acyltransferases related to lecithin-cholesterol acyltransferase. Subfamilies transfer an acyl chain from phospholipid to different acceptors: diacylglycerol for phospholipid:diacylglycerol acyltransferase (S. cerevisiae LRO1, S. pombe plh1; SF105), cholesterol for LCAT, and 1-O-acylceramide for lysosomal phospholipase A2 (PLA2G15). Other members include S. cerevisiae TGL2 and YJR098C.

Cytosolic type I thymidine kinases phosphorylate thymidine to dTMP in pyrimidine salvage. They are cell-cycle regulated in animals. The family contains bacterial Tdk, human TK1, poxvirus thymidine kinases and plant TK1 isozymes. S. cerevisiae and S. pombe have no member.

Porphobilinogen synthases condense two molecules of 5-aminolevulinate to porphobilinogen, the first common step of tetrapyrrole synthesis. Animal and fungal enzymes are zinc-dependent, plant and many bacterial ones Mg2+. The family contains bacterial HemB, S. cerevisiae HEM2, S. pombe hem2 and human ALAD.

Monofunctional heme catalases disproportionate hydrogen peroxide to water and oxygen. S. cerevisiae has a peroxisomal (and mitochondrial) catalase A (CTA1) and a cytosolic catalase T (CTT1). The family also contains S. pombe cta1, bacterial KatA/KatE, animal CAT and plant isozymes.

PLP-dependent alpha-glucan phosphorylases release glucose 1-phosphate from the non-reducing ends of alpha-1,4-glucans. The family contains glycogen phosphorylases (S. cerevisiae GPH1, human PYGL/PYGM/PYGB, bacterial GlgP), plant starch phosphorylases and E. coli maltodextrin phosphorylase MalP.

The conventional (SIS-domain) glucose-6-phosphate isomerases of bacteria and eukaryotes, which reversibly interconvert D-glucose 6-phosphate and D-fructose 6-phosphate: the second step of glycolysis and, run in reverse, a step of gluconeogenesis. Characterized members include E. coli Pgi, S. cerevisiae PGI1, S. pombe pgi1, human GPI and the cytosolic and plastid isozymes of plants. Vertebrate GPI is also secreted and acts extracellularly as neuroleukin / autocrine motility factor, a lineage-specific moonlighting role.

PANTHER family PTHR11471 encompasses metazoan tumor necrosis factor (TNF) superfamily ligands that share a C-terminal beta-jellyroll TNF-homology domain (THD) and assemble as non-covalent homotrimers (or LTA/LTB heterotrimers), generally synthesized as type II transmembrane proteins that can also be proteolytically shed as soluble extracellular cytokines. At the molecular-function and parent signaling level, the family is unified by extracellular or cell-surface cytokine activity (GO:0005125), tumor necrosis factor receptor superfamily binding (GO:0005164), and cell surface receptor signaling pathway (GO:0007166). However, individual subfamilies engage distinct TNFR-superfamily receptors with divergent intracellular signaling architectures: death-receptor ligands such as FASLG (SF33, engaging FAS/CD95) and TNFSF10/TRAIL (SF27, engaging TNFRSF10A/DR4 and TNFRSF10B/DR5) directly assemble FADD/caspase-8 death-inducing signaling complexes (DISCs) to execute extrinsic apoptosis (GO:0008625, GO:0036337, GO:0036462); TNF (SF23) and LTA (SF31) engage TNFR1/TNFR2 to balance complex-I NF-kappaB inflammatory signaling and complex-II apoptosis/necroptosis (GO:0033209); and TRAF-coupled costimulatory/developmental ligands such as CD40LG (SF5, engaging CD40) and TNFSF11/RANKL (SF3, engaging RANK/TNFRSF11A) drive B-cell activation/isotype switching and osteoclast differentiation (GO:0045672) without death domains.

Aromatic amino-acid hydroxylases use reduced pterin and oxygen to hydroxylate aromatic substrates. Phenylalanine hydroxylase produces tyrosine, tyrosine hydroxylase produces L-DOPA and tryptophan hydroxylase produces 5-hydroxytryptophan. These homologous reactions feed different metabolic and signaling pathways.

Animal-type heme-peroxidase relatives use or resemble enzymes that use peroxide in diverse extracellular reactions. Thyroid hormone synthesis, antimicrobial oxidant production, chorion modification and extracellular matrix cross-linking are distinct physiological contexts. Additional extracellular domains and active-site integrity are essential for distinguishing these roles.

Fold-type III PLP decarboxylases. Ornithine decarboxylase (S. cerevisiae SPE1, S. pombe spe1, bacterial SpeC, plant ODC, human ODC1) makes putrescine, the first step of polyamine synthesis. The antizyme inhibitors AZIN1 and AZIN2 are ODC paralogs that bind antizyme and so free ODC from antizyme-mediated degradation. AZIN1 has no decarboxylase activity; AZIN2 activity is disputed.

Alpha/beta-hydrolase type II thioesterases that release acyl chains from acyl carrier proteins or phosphopantetheinyl arms. Human OLAH releases medium-chain fatty acids from fatty acid synthase in mammary gland; bacterial TesA-type enzymes edit polyketide and nonribosomal peptide synthases.

Siroheme/[4Fe-4S] hemoproteins that carry out the six-electron reduction of sulfite to sulfide. The main subfamily (SF47) contains the assimilatory sulfite reductase catalytic subunits of three electron-supply architectures: the enterobacterial NADPH enzyme CysI (paired with the CysJ flavoprotein), the fungal NADPH enzyme beta subunit MET5/ECM17 of S. cerevisiae and sir1 of S. pombe (paired with MET10, and itself carrying an extra flavodoxin-like FMN domain), and the plastid ferredoxin-dependent sulfite reductases of plants (Arabidopsis SIR, maize, soybean), which take electrons directly from ferredoxin. A small second subfamily (SF54) holds anaerobic sulfite reductase subunit C (Salmonella AsrC) and dissimilatory-type sulfite reductase alpha subunits (Desulfovibrio DsvA, Archaeoglobus DsrA).

Small family of type I transmembrane immunoglobulin-superfamily co-receptors of T lymphocytes, comprising the activating costimulatory receptor CD28 (subfamily SF7) and the inhibitory checkpoint receptor CTLA-4 (subfamily SF8). Members share the same architecture (a single extracellular IgV domain carrying the MYPPPY ligand-binding motif, a transmembrane segment, and a short cytoplasmic tail), form disulfide-linked homodimers, sit on the external side of the plasma membrane, and bind the same two B7 ligands, CD80 (B7-1) and CD86 (B7-2), on antigen-presenting cells. What they do with that shared ligand engagement is opposite. CD28 delivers "signal 2": its cytoplasmic YMNM and PYAP motifs recruit PI3K and GRB2/Lck, amplifying TCR signaling and driving IL-2 production, T cell proliferation and activation (coreceptor activity, GO:0015026). CTLA-4 binds the same ligands with higher avidity and shuts costimulation down: it acts as a ligand-sequestering decoy (receptor decoy activity, GO:0140319), removes CD80/CD86 from APCs by transendocytosis, and its YVKM motif recruits phosphatases that attenuate TCR-proximal signaling (PMID:11279501, PMID:11279502). The family is therefore an object lesson for phylogenetic propagation: ligand, topology, localization and direction-neutral pathway-participation terms are conserved family-wide, while every signaling-direction term (costimulation, positive/negative regulation of T cell activation or proliferation, and the two opposite molecular-function terms) is safe only within one subfamily. InterPro (IPR040216) counts 1947 proteins in 3 subfamilies across 2257 taxa; the reviewed slice contains only mammalian/avian CD28 (SF7) and mammalian CTLA4 (SF8) orthologs, so the third subfamily (the broader family is usually described as also containing the ICOS-like activating receptors) is not represented among reviewed members and is not adjudicated here.

Members of the iron-containing alcohol dehydrogenase fold (group III ADHs), unrelated in structure to the zinc medium-chain ADHs. Characterized NAD(H)-dependent alcohol dehydrogenases in the family include Zymomonas mobilis ADH II (adhB), the major fermentative ADH of that bacterium; S. cerevisiae ADH4, a minor, zinc-induced isozyme reported as mitochondrial; fission yeast adh4, a mitochondrial-matrix ethanol dehydrogenase that also sustains ethanol fermentation in adh1 null cells; E. coli FucO (lactaldehyde reductase), EutG, YiaY and the alcohol dehydrogenase domain of AdhE; and Klebsiella/Citrobacter 1,3-propanediol dehydrogenase DhaT. The same fold is used by enzymes that are not ordinary alcohol dehydrogenases: maleylacetate reductases of chloroaromatic degradation, methanol: N,N-dimethyl-4-nitrosoaniline oxidoreductases, sulfoacetaldehyde and phosphonoacetaldehyde reductases, Kdo 8-oxidase (KdnB), and the animal mitochondrial hydroxyacid-oxoacid transhydrogenase ADHFE1.

Secreted cystine-knot glycoprotein hormone alpha subunits (InterPro:IPR001545) comprising the common vertebrate pituitary/placental glycoprotein hormone alpha chain (CGA, PANTHER:PTHR11509:SF0) and the ancestral bilaterian glycoprotein hormone alpha-2 subunit (GPHA2/GPA2). In jawed vertebrates, CGA non-covalently heterodimerizes with four hormone- specific beta subunits (PANTHER:PTHR11515)—TSHB, FSHB, LHB, and primate CGB—to assemble thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and chorionic gonadotropin (hCG), respectively, whereas GPHA2 heterodimerizes with GPHB5 to form thyrostimulin. Within each heterodimer, the alpha subunit makes direct contact with both the extracellular leucine-rich repeat domain and the hinge/transmembrane domain of the cognate GPCR (TSHR, FSHR, or LHCGR; PANTHER:PTHR24372) and is essential for receptor activation and signal transduction (GO:0038194, GO:0042699, and GO:0042700).

NAD-dependent inositol-3-phosphate synthases cyclize glucose 6-phosphate to myo-inositol 3-phosphate, the only de novo route to inositol. The family contains S. cerevisiae INO1 (whose expression is controlled by the Ino2/Ino4-Opi1 circuit), S. pombe ino1, human ISYNA1 and plant MIPS.

Secreted cystine-knot glycoprotein hormone beta subunits (InterPro:IPR001545) that non-covalently heterodimerize with a shared glycoprotein hormone alpha subunit (CGA in jawed vertebrates, PANTHER:PTHR11509; GPA2/GPHA2 in the ancestral thyrostimulin system) to form active endocrine heterodimers. Whereas the common alpha subunit provides conserved scaffolding and receptor-activation determinants, the paralogous beta subunits confer strict receptor specificity across leucine-rich-repeat G protein-coupled receptors (PANTHER:PTHR24372): thyrotropin subunit beta (TSHB, PANTHER:PTHR11515:SF5) directs binding to the thyroid-stimulating hormone receptor (TSHR) to initiate the thyroid-stimulating hormone signaling pathway (GO:0038194); follitropin subunit beta (FSHB, PANTHER:PTHR11515:SF17) directs binding to FSHR in the follicle-stimulating hormone signaling pathway (GO:0042699); lutropin/choriogonadotropin beta subunits (LHB and primate CGB paralogs, PANTHER:PTHR11515:SF11 and SF25) direct binding to LHCGR in the luteinizing hormone signaling pathway (GO:0042700); and glycoprotein hormone beta-5 (GPHB5, PANTHER:PTHR11515:SF14) pairs with GPHA2 to form thyrostimulin, an ancestral agonist of TSHR.

The thiamine-diphosphate-binding alpha subunit of the alpha2beta2 E1 component of pyruvate dehydrogenase. The family contains S. cerevisiae PDA1, S. pombe pda1, human PDHA1 and testis PDHA2, and plant mitochondrial and plastid E1 alpha. Bacterial acetoin dehydrogenase E1 alpha (AcoA) is also placed here.

Farnesyl diphosphate synthases condense IPP with DMAPP and then geranyl diphosphate to make (2E,6E)-farnesyl diphosphate, the branch point for sterols, ubiquinone side chains and prenylation. The family contains S. cerevisiae ERG20, S. pombe fps1, human FDPS and plant FPS. It also contains S. pombe spo9, an inactive FPS-like protein that partners with the GGPS to make geranylgeranyl diphosphate for sporulation.

Small heat-shock proteins and alpha-crystallins form oligomeric assemblies that interact with non-native proteins. Client recognition, oligomer structure, expression response and cellular localization vary among organisms and paralogs.

NAD-dependent L-malate dehydrogenases interconvert malate and oxaloacetate. S. cerevisiae has three compartment-specific isozymes: mitochondrial MDH1 (TCA cycle), cytosolic MDH2 (gluconeogenesis and glyoxylate cycle) and peroxisomal MDH3. The family also contains S. pombe mdh1, human mitochondrial MDH2, bacterial Mdh and plant mitochondrial and peroxisomal MDHs.

ThyA-type thymidylate synthases catalyse the reductive methylation of dUMP to dTMP, using 5,10-methylenetetrahydrofolate as both the one-carbon donor and the reductant and releasing 7,8-dihydrofolate. This is the only de novo route to thymidylate. The family spans bacteria (E. coli and M. tuberculosis ThyA, the two B. subtilis paralogs), fungi (S. cerevisiae CDC21), animals (TYMS) and the bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) proteins of plants and protists, in which a DHFR domain is fused N-terminal to the TS domain. Fission yeast has an unusual fusion: hal3 (SPAC15E1.04) joins a Hal3-like phosphopantothenoylcysteine decarboxylase (PPCDC) domain to a C-terminal TS domain, and PANTHER classifies the whole protein in this family (SF2). The family also holds a small number of phage enzymes, the dUMP hydroxymethylases of Bacillus phage SPO1 and Pseudomonas phage M6, which use the same chemistry to make 5-hydroxymethyl-dUMP instead of dTMP.

CTP synthases aminate UTP to CTP, using glutamine (or ammonia) and ATP. This is the only de novo route to CTP. The enzyme has an N-terminal amidoligase domain and a C-terminal class I glutamine amidotransferase domain. It is regulated by assembly from dimers into tetramers, by GTP activation and by CTP feedback inhibition. In many eukaryotes and bacteria it also polymerizes into filaments (cytoophidia). Bacteria (PyrG), fungi (S. cerevisiae URA7 and URA8, S. pombe ura7/cts1), plants and animals (CTPS1, CTPS2) all have members. In S. cerevisiae URA7 is the major isozyme, and loss of both URA7 and URA8 is lethal.

The GMC oxidoreductases are FAD-dependent enzymes with an N-terminal Rossmann-type FAD-binding domain and a C-terminal substrate-binding domain. They oxidize alcohols (CH-OH donors) and related substrates, passing the electrons either to O2 (oxidases) or to quinones and other acceptors (dehydrogenases). The family includes bacterial BetA and vertebrate mitochondrial choline dehydrogenases (CHDH), choline oxidase, fungal glucose oxidases and pyranose dehydrogenases, yeast methanol (alcohol) oxidases, insect ecdysone oxidase, the algal fatty-acid photodecarboxylase, and many fungal oxidoreductases that work in secondary-metabolite gene clusters. FAD-dependent oxidoreduction is common to the whole family. Substrate, acceptor and pathway are not, so specific activity terms apply only within clades. The choline dehydrogenases (BetA/CHDH) use a non-NAD acceptor, and no member is an NAD-dependent dehydrogenase.

Class I fructose-1,6-bisphosphatases hydrolyse fructose 1,6-bisphosphate to fructose 6-phosphate, the committed step of gluconeogenesis that bypasses phosphofructokinase. The family contains S. cerevisiae FBP1, animal FBP1/FBP2, plant cytosolic and plastid FBPases, bacterial Fbp, and plastid sedoheptulose-1,7-bisphosphatase (Calvin cycle).

Porphobilinogen deaminases polymerize four porphobilinogen units on a dipyrromethane cofactor to make hydroxymethylbilane, the linear tetrapyrrole precursor of uroporphyrinogen III (bacterial HemC, S. cerevisiae HEM3, S. pombe hem3, human HMBS).

Aminopropyltransferases transfer the aminopropyl group of decarboxylated S-adenosylmethionine to an amine. Spermidine synthase uses putrescine (bacterial SpeE, S. cerevisiae SPE3, S. pombe SPBC12C2.07c, human SRM). Spermine synthase uses spermidine (S. cerevisiae SPE4, plant SPMS). Plant putrescine N-methyltransferases (PMT) evolved from spermidine synthase and transfer a methyl group from SAM instead.

PTHR11564 contains the signal-sequence-binding GTPase subunit of the signal recognition particle (SRP) in all three domains of life: eukaryotic and archaeal SRP54 and bacterial Ffh. Members share an N-terminal N domain that contacts the ribosome, a central Ras-like G domain that binds and hydrolyses GTP, and a C-terminal methionine-rich M domain that binds both the SRP RNA (7SL/7S RNA in eukaryotes, 4.5S RNA in most bacteria) and the hydrophobic signal or signal-anchor sequence of a nascent chain emerging from the ribosome. The NG module heterodimerizes with the homologous NG module of the SRP receptor (SR alpha or bacterial FtsY, PTHR43134) in a GTP-dependent manner, forming a shared active site in which both GTPases are reciprocally activated; this drives handoff of the ribosome-nascent chain to the Sec61/SecYEG translocon and recycling of the targeting factors.

Pyruvoyl-dependent S-adenosylmethionine decarboxylases make decarboxylated SAM, the aminopropyl donor for spermidine and spermine synthesis. The proenzyme self-cleaves to form the pyruvoyl group. The family contains S. cerevisiae SPE2, S. pombe spe2, human AMD1 and plant SAMDCs, and the inactive trypanosome prozyme, which activates the catalytic subunit.

Class I ribonucleotide reductases (RNRs) reduce ribonucleoside diphosphates (ADP, GDP, CDP, UDP) to the corresponding 2'-deoxyribonucleoside diphosphates. This is the committed step of de novo deoxyribonucleotide synthesis. The enzyme is an alpha2beta2 complex. The large (alpha, R1) subunit in this family binds substrate and the allosteric specificity effectors and carries the catalytic cysteines; most members also have an N-terminal ATP-cone activity site. The small (beta, R2) subunit (PTHR23409) generates and stores the tyrosyl radical that starts each turnover. The family spans eukaryotic R1 (yeast Rnr1 and Rnr3, fission yeast Cdc22, human RRM1), bacterial class Ia NrdA (E. coli) and class Ib NrdE (E. coli, B. subtilis, M. tuberculosis). In S. cerevisiae a DNA-damage-inducible paralog, Rnr3, has very low activity on its own but is stimulated when it forms an Rnr1/Rnr3 heterodimer.

Vertebrate (Euteleostomi) family of short-chain four-helix-bundle cytokines orthologous to mammalian KITLG (stem cell factor, SCF; steel factor; mast cell growth factor). Synthesized as single-pass type I transmembrane precursors that form non-covalent homodimers at the plasma membrane and undergo regulated proteolytic shedding to release soluble homodimeric cytokines. Both membrane-bound and soluble forms bind the extracellular immunoglobulin-like domains (D1-D3) of the receptor tyrosine kinase KIT, driving receptor homodimerization, trans-autophosphorylation, and downstream Kit signaling in hematopoietic stem and progenitor cells, mast cells, melanocyte precursors, primordial germ cells, and interstitial cells of Cajal. Teleosts retain two co-orthologs from the teleost whole-genome duplication (kitlga and kitlgb in Danio rerio) that partition the splice-isoform and developmental functions of tetrapod KITLG.

This family combines cytoplasmic tyrosyl-tRNA synthetases with related tRNA-binding or regulatory proteins, including AIMP1-type factors. Complete TyrRS enzymes activate tyrosine with ATP and transfer it to cognate tRNA. Shared ancillary RNA-binding domains do not confer that aminoacylation reaction on a protein lacking the synthetase module.

Type-1 argininosuccinate synthases, the ATP-dependent enzymes that condense L-citrulline and L-aspartate to argininosuccinate, the penultimate step of L-arginine biosynthesis. The family spans bacterial and cyanobacterial ArgG, fungal ARG1/arg12, plant chloroplastic ASS and animal ASS1. All PAINT IBD assertions sit at one root node (PTN000172504): argininosuccinate synthase activity, L-arginine biosynthesis, cytosol and urea cycle, with a negated urea-cycle IRD for the protostome clade. The catalytic and biosynthetic assertions are sound family-wide; the urea-cycle assertion holds only in lineages whose arginase closes the cycle, and is placed too deep for bacteria that recycle or degrade arginine by other routes.

Tubulin-family GTP-binding proteins form or organize microtubule structures. Alpha/beta heterodimers make the microtubule lattice, whereas gamma-tubulin supports nucleation and other tubulin classes have specialized centriole or basal-body roles. Isotype-specific expression and lattice properties add a further level of divergence.

GPX-fold proteins reduce peroxide substrates using distinct electron-donor systems. The family includes glutathione-dependent enzymes, thioredoxin-supported enzymes, cysteine and selenocysteine forms, and specialized secretory-pathway members.

A metallo-phosphomonoesterase family that hydrolyses phosphate monoesters at alkaline pH through a covalent phosphoseryl intermediate, present from bacteria to vertebrates. Catalysis is carried out by a trinuclear metal centre of two Zn(2+) and one Mg(2+) together with an invariant active-site serine, and every reviewed member of the family retains that serine in an essentially unchanged D-S-A/G context. There is no known pseudo-enzyme branch here: unlike families where a catalytic residue has been lost in one lineage, this one has kept its chemistry intact everywhere it has been examined. What has diverged is not the reaction but where it is performed and what it is performed on. Bacteria secrete the enzyme into the periplasm for phosphate scavenging; fungi relocated it to the vacuole membrane; animals bolted it to the outer leaflet of the plasma membrane through a C-terminal GPI anchor, making it an ectoenzyme that acts on extracellular substrates. Animals also gained a structural Ca(2+) site and a crown domain that have no counterpart in the bacterial enzyme. In bony vertebrates the tissue-nonspecific branch was then recruited to skeletal mineralization, where it destroys extracellular pyrophosphate, and the tissue-specific branch duplicated into the intestinal, placental and germ-cell isozymes. The family is therefore a case where an IBA for the molecular function is safe everywhere and IBAs for compartment and process are safe only within their own clades -- which is exactly how PAINT has scoped them.

PLP-dependent fold-type I aminotransferase-like enzymes that remove sulfur from L-cysteine, forming L-alanine and a persulfide on a conserved active-site loop cysteine, and pass that sulfur to acceptor proteins. The dominant subfamily SF34 contains bacterial IscS (housekeeping Fe-S cluster assembly and sulfur donor for tRNA thiolation, thiamine and molybdopterin biosynthesis), the nitrogenase-specific NifS proteins, and eukaryotic mitochondrial NFS1. Two small bacterial subfamilies (SF36 NifS-related and SF50 IscS2-related, mainly Firmicutes) are cysteine desulfurases of less characterized pathways. The vertebrate selenocysteine lyases (SF62, SCLY) are the diverged branch: they decompose L-selenocysteine to L-alanine and selenide and are essentially inactive on L-cysteine.

Glutamate dehydrogenases interconvert glutamate and 2-oxoglutarate plus ammonia. The family contains animal GLUD1/GLUD2, which use NAD+ or NADP+ and are allosterically regulated by ADP and GTP in the mitochondrial matrix, and the large NAD-specific GDHs of fungi and plants (S. cerevisiae GDH2, S. pombe gdh2), which mainly catabolize glutamate.

This family is defined by the PurK-type ATP-grasp N5-carboxyaminoimidazole ribonucleotide (N5-CAIR) synthetase. In bacteria, yeasts and plants the carboxylation of 5-aminoimidazole ribonucleotide (AIR) to 4-carboxy-AIR (CAIR) takes two half-reactions. PurK uses ATP and bicarbonate to carbamylate the AIR exocyclic amine, giving N5-CAIR, and a class I PurE mutase then moves the carboxylate onto C4 of the ring. Bacterial members (E. coli, B. subtilis, Pseudomonas PurK) are standalone N5-CAIR synthetases with a separate PurE partner. Fungal ADE2 (S. cerevisiae Ade2, S. pombe ade6, Candida and Cryptococcus ADE2) and plant PURKE proteins fuse an N-terminal PurK domain to a C-terminal class I PurE domain, so one polypeptide carries out both half-reactions. Dictyostelium purC/E fuses a SAICAR synthetase domain, a PurE domain and a PurK domain. None of these proteins catalyses the class II direct, ATP-independent carboxylation of AIR with CO2 that animal PAICS performs.

PTHR11610 collects the animal lipases built on the pancreatic-lipase fold: an N-terminal alpha/beta-hydrolase catalytic domain carrying a Ser-Asp-His triad under a mobile surface "lid", plus a C-terminal PLAT/beta-sandwich domain that mediates interfacial and cofactor interactions. All members are secreted and all are ester hydrolases acting at a lipid-water interface, which is what the deep PAINT node PTN008325466 records (lipase activity, lipid catabolic process, extracellular region) and what is genuinely shared. Above that shared floor the family splits into groups whose substrates, cofactors and anatomical compartments are different. The exocrine pancreatic branch (PNLIP, PNLIPRP1, PNLIPRP2) is secreted into the gut lumen, hydrolyses emulsified dietary triacylglycerol, and depends on colipase to work in the presence of bile salts. The vascular branch (lipoprotein lipase, hepatic lipase, endothelial lipase) is heparan-sulfate-anchored at the endothelial surface, acts on triacylglycerol and phospholipid carried in circulating lipoprotein particles, uses apolipoprotein cofactors such as apoC-II, and is the branch that remodels VLDL, chylomicrons and HDL. A third branch (LIPH, LIPI, PLA1A) has specialised as phospholipases A1 that generate lysophospholipid signalling molecules. Chimera experiments locate much of the triacylglycerol-versus-phospholipid preference in the lid rather than in the triad, so substrate specificity in this family is a surface property of an otherwise conserved catalytic machine. A consequence that matters for annotation: catalytic-residue loss is not the discriminator anywhere in this family. Every member checked here retains an intact Ser-Asp-His triad, including human PNLIPRP1, which is named "inactive" and has no demonstrated lipase activity. Differences between the branches therefore have to be argued from substrate, cofactor and compartment, not from a degraded active site.

NARF and NARFL/Nar1-related proteins illustrate functional divergence among hydrogenase-related proteins. Human NARF binds prenylated prelamin A, whereas NARFL/IOP1 has direct support in cytosolic iron-sulfur protein maturation. Broad structural relationships do not establish respiratory hydrogenase chemistry or identical Fe-S assembly roles.

The beta subunit of the alpha2beta2 E1 component of mitochondrial pyruvate dehydrogenase (S. cerevisiae PDB1, S. pombe pdb1, human PDHB, plant E1 beta). With E1 alpha it decarboxylates pyruvate and transfers the acetyl group to the lipoyl arm of E2.

Squalene synthases are ER-membrane enzymes that join two molecules of farnesyl diphosphate head to head, via presqualene diphosphate, and reduce the product with NAD(P)H to squalene. This is the first committed step of sterol synthesis. The family contains the single-copy squalene synthases of fungi (S. cerevisiae ERG9, S. pombe erg9), animals (FDFT1) and plants (Arabidopsis SQS1), and several divergent paralogs. Arabidopsis SQS2 has no squalene synthase activity, and Botryococcus braunii has squalene synthase-like enzymes that split the two half-reactions or make other triterpenes (botryococcene, lycopaoctaene).

Class I fructose-bisphosphate aldolases cleave D-fructose 1,6-bisphosphate to dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate through a Schiff-base intermediate on an active-site lysine, with no metal cofactor. The family holds the animal, plant and some bacterial aldolases: the vertebrate isozymes A, B and C, invertebrate aldolases (Drosophila Ald1, C. elegans aldo-1 and aldo-2), and the Arabidopsis cytosolic (FBA4 to FBA8) and chloroplastic (FBA1 to FBA3) isoforms. The same reaction is catalysed by the unrelated metal-dependent class II aldolases of fungi and most bacteria (PTHR30559). Vertebrate aldolase B also cleaves fructose 1-phosphate efficiently, the step that makes it the aldolase of dietary fructose catabolism in liver, kidney and intestine.

MCM-family ATPases include the MCM2-7 replicative helicase subunits and MCM8/9-associated DNA repair factors. Eukaryotic MCM2-7 functions as a heterohexamer within the active replisome, with different subunits contributing to an assembled motor. Related MCM8/9 proteins do not simply substitute for replication-licensing subunits.

Covalent-FAD flavoproteins that oxidize succinate to fumarate (complex II SDHA: S. cerevisiae SDH1 and its paralog YJL045W, S. pombe sdh1, human SDHA, bacterial SdhA) or reduce fumarate (bacterial FrdA). PANTHER also places the alpha subunit of adenylylsulfate reductase (AprA) of sulfate-reducing bacteria in this family.

Immunoglobulin-domain extracellular and cell-surface proteins in this grouping mediate adhesion, recognition or tissue organization. The nephrin/Sns branch contributes to specialized cell junctions and, in flies, myoblast recognition and fusion. Other branches include different adhesion receptors and larger extracellular matrix proteins.

Cytidine-deaminase-related proteins use a zinc-dependent deamination scaffold with divergent substrates. The grouping includes conventional nucleoside deaminases and blasticidin-S deaminases, as well as plant relatives whose catalytic competence is uncertain.

NAD(P)H-dependent 1-pyrroline-5-carboxylate (P5C) reductases, which catalyse the last step of proline biosynthesis and also reduce the P5C produced from ornithine. The family contains bacterial ProC, Bacillus ProH/ProI/ProG, fungal PRO3/pro3, plant P5CR, and the three human paralogs PYCR1 and PYCR2 (mitochondrial) and PYCR3 (cytosolic, in the same subfamily as the yeast and bacterial enzymes). PANTHER also places some divergent proteins with the same Rossmann fold-like N-terminal domain here: archaeal Hmd (the iron-sulphur cluster-free hydrogenase, inside SF0), Bacillus ComER (SF51) and human NOXRED1 (SF58).

Metal-dependent cyclic amidohydrolases of the amidohydrolase superfamily and their inactive paralogs. Active members include the eukaryotic dihydropyrimidinases (human DPYS, plant, yeast, Dictyostelium and nematode enzymes) and bacterial dihydropyrimidinases and D-hydantoinases such as Pseudomonas putida KT2440 PydB, which open the 5,6-dihydropyrimidine ring in the second step of reductive pyrimidine degradation. The family also contains the vertebrate collapsin response mediator proteins (CRMP1 and DPYSL2-5) and C. elegans UNC-33, which keep the fold but lost catalysis and act in axon guidance and cytoskeletal regulation, plus bacterial isoaspartyl dipeptidase, D-phenylhydantoinase, acyl-D-amino-acid deacylases, enamidase and archaeal formylmethanofuran dehydrogenase subunit FwdA.

PTHR11654 is the proton-coupled oligopeptide transporter (POT, also PTR or SLC15) family of the major facilitator superfamily: 12-transmembrane-helix secondary transporters found in bacteria, fungi, animals and plants. Outside plants, characterized members are mostly H+-coupled di- and tripeptide transporters (bacterial DtpA-D, yeast PTR2, mammalian SLC15A1/PEPT1 and SLC15A2/PEPT2; SLC15A3/A4 are endolysosomal peptide/histidine transporters). In land plants the family expanded into the NRT1/PTR FAMILY (NPF; 53 members in Arabidopsis, eight clades NPF1-NPF8). Only the NPF8 clade has kept di/tripeptide transport as its predominant activity (NPF8.1/PTR1, NPF8.2/PTR5, NPF8.3/PTR2; NPF8.4 transports glycerate). The other clades transport, often more than one at a time, nitrate, nitrite, chloride, potassium, glucosinolates and cyanogenic glucosides, alkaloids, flavonoids, nicotianamine, sugars and the hormones ABA, gibberellins, jasmonoyl-isoleucine, IAA and IBA, and some (NPF6.3/NRT1.1, rice NRT1.1B) also act as nitrate sensors. Nitrate and gibberellin transport are scattered across clades rather than confined to one, and paralogs within a clade frequently differ, so membership in the family or in an NPF clade does not predict substrate. What is conserved family-wide is the MFS fold and transmembrane transporter activity; the TM1 ExxE[R/K] proton-coupling motif is conserved in most members but absent from the NPF2a subclade and the NPF7 clade.

Clamp-loader-related ATPases assemble sliding clamps on nucleic acids to support processive DNA synthesis and repair. Eukaryotic RFC complexes combine several small subunits with alternative large subunits; related bacterial clamp-loader components and plant Stichel proteins broaden the family beyond one canonical replication complex.

[4Fe-4S] hydro-lyases of the aconitase/IPM isomerase superfamily. The family comprises the AcnA-type aconitases of bacteria (Escherichia coli and Salmonella AcnA, Bacillus subtilis CitB, Mycobacterium Acn, Corynebacterium Acn), the cytosolic aconitases and iron-regulatory proteins of eukaryotes (human ACO1/IRP1 and IREB2/IRP2), plant aconitases, and the AcnD 2-methylcitrate dehydratases of the AcnD/PrpF branch of the bacterial 2-methylcitrate cycle (Shewanella oneidensis, Vibrio cholerae, Pseudomonas putida). Canonical members interconvert citrate and isocitrate. As apo-proteins, several bind RNA: the vertebrate IRPs bind iron-responsive elements, and bacterial AcnA binds the 3' untranslated regions of acnA and acnB mRNA. Salmonella AcnA also hydrates 2-methyl-cis-aconitate to 2-methylisocitrate. AcnD has diverged: it dehydrates 2-methylcitrate and citrate but does not use isocitrate or 2-methylisocitrate, and it cannot replace aconitase in the TCA cycle.

PLP-dependent SHMTs reversibly transfer the hydroxymethyl group of serine to tetrahydrofolate, making glycine and 5,10-methylene-THF, the main source of one-carbon units. Eukaryotes have cytosolic and mitochondrial isozymes (S. cerevisiae SHM2 and SHM1, human SHMT1 and SHMT2); bacteria have GlyA.

Ntn-hydrolase gamma-glutamyltransferases cleave the gamma-glutamyl bond of glutathione and its conjugates, either hydrolysing it or transferring the gamma-glutamyl group to an acceptor. Animal GGT1 is a plasma-membrane ectoenzyme. S. cerevisiae ECM38/CIS2 and S. pombe ggt1/ggt2 are vacuolar and degrade glutathione.

PurH (bacteria) and ATIC/ADE16/ADE17/ade10 (eukaryotes) catalyse the last two steps of de novo IMP synthesis. An N-terminal domain closes the purine ring (IMP cyclohydrolase, FAICAR to IMP) and a C-terminal domain transfers a formyl group from 10-formyltetrahydrofolate to AICAR (AICAR transformylase). The enzyme is a cytosolic homodimer in the characterized species. Every reviewed PANTHER member (472 entries, bacteria, fungi, plants and animals, 452 to 605 residues) sits in the single subfamily SF0. S. cerevisiae has two isozymes, ADE16 and ADE17, either of which suffices for growth without adenine; ADE17 is repressed by adenine. Loss of both also causes histidine auxotrophy, because AICAR is a by-product of histidine biosynthesis.

The aldehyde dehydrogenases share a conserved three-domain architecture -- a Rossmann-fold NAD(P)+-binding domain, a catalytic domain, and a smaller oligomerization domain -- and oxidize aldehydes to their carboxylic acids through a covalent thio(hemi)acetal intermediate formed at a catalytic cysteine nucleophile, with a conserved glutamate acting as general base. The family is old and broad: the deepest cached PAINT node for NAD+-dependent aldehyde dehydrogenase activity is seeded by bacterial, fungal, plant and animal members, and 47 PANTHER subfamilies span substrate specialists as different as retinaldehyde dehydrogenases (the ALDH1A/RALDH branch, source of embryonic retinoic acid), mitochondrial acetaldehyde-preferring ALDH2, betaine-aldehyde and succinate-semialdehyde dehydrogenases, acylating acetaldehyde dehydrogenases (EutE), 10-formyltetrahydrofolate dehydrogenase fusion proteins (ALDH1L), and at least one member with degenerate active-site residues (ALDH16A1). The ALDH1L proteins are multidomain fusion enzymes: an N-terminal folate-binding hydrolase/formyltransferase-like domain and a 4'-phosphopantetheine carrier domain deliver the formyl group of 10-formyl-THF to a C-terminal ALDH domain that oxidizes it to CO2 using NADP+, not NAD+; vertebrates carry a compartment-split ALDH1L paralog pair -- cytosolic ALDH1L1 and mitochondrial ALDH1L2, the latter distinguished by an N-terminal mitochondrial transit peptide acquired in its own lineage. Generic aldehyde-oxidation chemistry is close to family-wide; substrate identity, cofactor preference (NAD+ vs NADP+), localization and pathway context are not, and are the properties that distinguish subfamilies -- which is why family- or deep-node-level propagation of NAD+ cofactor terms or of a compartment term is unsafe even though the catalytic fold and the Cys/Glu machinery are conserved.

NRAMP/SLC11 proteins are proton-coupled divalent metal transporters found across bacteria, fungi, plants and animals. Characterized members move Fe(2+), Mn(2+) and other divalent cations across plasma, endosomal or vacuolar membranes: human SLC11A2 (DMT1) mediates dietary iron uptake and endosomal iron export, human SLC11A1 acts in phagosomal metal handling, yeast SMF1/SMF2 transport manganese, and plant NRAMPs (Arabidopsis NRAMP1-6, poplar NRAMP1-7) mobilize iron and manganese between the vacuole, plastids and the cytosol. One clade is not a transporter at all. The land-plant EIN2 proteins (subfamily SF75) carry an NRAMP-like N-terminal integral-membrane domain but have appended a large C-terminal cytoplasmic extension, roughly doubling the protein length (the reviewed transporter subfamilies run 500-581 aa in the fetched slice, all non-EIN2 members 397-696 aa; EIN2 members run 1281-1294 aa). EIN2 is the central transducer of ethylene signaling at the endoplasmic reticulum membrane: ethylene perception triggers cleavage and nuclear/cytoplasmic translocation of its C-terminal fragment. No metal transport activity has been demonstrated for any EIN2, so transport and metal-homeostasis terms placed on deep family nodes must not descend into SF75.

Asparaginase/glutaminase-fold amidohydrolases that hydrolyse L-asparagine to L-aspartate and ammonium (EC 3.5.1.1). In the UniProt/InterPro member inventory all reviewed members fall in a single subfamily, SF28 (official name "60 KDA LYSOPHOSPHOLIPASE"), which mixes bacterial cytoplasmic type I enzymes (E. coli ansA), periplasmic type II enzymes (E. coli ansB, Pseudomonas glutaminase-asparaginases), the fungal enzymes (S. cerevisiae cytoplasmic ASP1 and cell-wall ASP3-1..4, four S. pombe paralogues), vertebrate ASPG (60 kDa lysophospholipase) and the archaeal GatD subunit of the Glu-tRNA(Gln) amidotransferase GatDE.

PTHR11711 collects the ADP-ribosylation factor (Arf) and Arf-like (Arl) small GTPases, a large branch of the Ras superfamily built on a P-loop G domain plus an N-terminal amphipathic helix that is myristoylated or acetylated and inserts into membranes when the protein is GTP-loaded. Members are not enzymes acting on a diffusible substrate: the conserved chemistry is the nucleotide cycle itself, and the biological output is the recruitment of effectors to a particular membrane. Intrinsic hydrolysis is slow and is completed by ArfGAPs, which supply an arginine finger in trans, so the G domain encodes the switch but not a fast turnover rate. The family name is historical -- Arf was named as a cofactor for cholera-toxin-catalysed ADP-ribosylation, not because its members ADP-ribosylate anything -- which is why a preferred_name is recorded alongside it. What differs between members is where the switch operates. The classical ARFs (ARF1-5) act at the Golgi and drive COPI and clathrin-adaptor recruitment; ARF6 works at the plasma membrane and endocytic compartments; ARL1 marks the TGN for golgin tethers; the ARL5 clade acts at the TGN, where it is recruited downstream of ARFRP1-SYS1 and in turn recruits the GARP tethering complex and the ARMH3-PI4KB module for endosome-to-TGN retrograde traffic; and ARL6/BBS3 has moved out of the secretory pathway altogether into BBSome-dependent ciliary transport. Nucleotide-binding terms are therefore safe across the whole family while compartment terms are not.

Beta-ketoacyl synthases extend acyl chains by condensation with activated malonyl donors. Related enzymes serve bacterial and organellar fatty-acid synthesis as well as specialized polyketide pathways. Product length and pathway context depend on the enzyme and its surrounding biosynthetic machinery. Related noncatalytic chain-length factors partner with the catalytic ketosynthase in aromatic polyketide synthesis.

The H protein of the glycine cleavage system carries a lipoyl arm that shuttles the aminomethyl intermediate and reducing equivalents between the P, T and L proteins. Eukaryotic H proteins also act as lipoyl donors for protein lipoylation. The family contains bacterial GcvH, S. cerevisiae GCV3, S. pombe gcv3 and human GCSH.

NAD(P)-dependent glycerol-3-phosphate dehydrogenases interconvert dihydroxyacetone phosphate and glycerol-3-phosphate while coupling to pyridine-nucleotide redox chemistry. Related paralogs serve glycerolipid metabolism, redox shuttling or lineage-specific glycerol production. They are distinct from the FAD-dependent mitochondrial shuttle enzyme.

NAD(P)H-dependent aldo-keto reductases with a (beta/alpha)8 barrel reduce a wide range of aldehydes and ketones. Subfamilies specialize: aldose/xylose reductases (S. cerevisiae GRE3, Scheffersomyces XYL1), D-arabinose dehydrogenase (S. cerevisiae ARA1), glycerol dehydrogenase (GCY1), and the animal steroid-metabolizing AKR1C (3-alpha-hydroxysteroid dehydrogenases such as AKR1C4) and AKR1D1 (steroid 5-beta-reductase).

M13 metallopeptidase relatives include neprilysins, endothelin-converting enzymes, PHEX and other extracellular or membrane-associated proteins. Characterized enzymes share a zinc-dependent proteolytic framework while differing substantially in peptide substrate selection and biological role.

Citrate synthases condense acetyl-CoA and oxaloacetate to citrate. S. cerevisiae has mitochondrial CIT1 (TCA cycle), peroxisomal CIT2 (glyoxylate cycle) and mitochondrial CIT3, which also makes 2-methylcitrate. S. pombe has cit1. The family also contains the bacterial PrpC 2-methylcitrate synthases of propionate catabolism.

Class I alpha-mannosidases trim alpha-1,2-linked mannose residues from N-linked glycans. Related enzymes act at different stages of secretory-pathway glycan maturation and quality control. Their location and preferred glycan branch determine whether a particular trimming event supports productive maturation or disposal of a substrate.

A large family of FAD-containing oxidoreductases with the PCMH-type (vanillyl-alcohol oxidase/p-cresol methylhydroxylase) FAD-binding fold. The family name reflects its best-characterized eukaryotic members, the mitochondrial FAD-dependent D-lactate dehydrogenases (yeast DLD1, Arabidopsis D-LDH, vertebrate LDHD; SF111), which oxidize D-lactate and other (2R)-2-hydroxyacids and pass electrons to cytochrome c. Bacterial subfamilies include the 4Fe-4S-containing D-2-hydroxyglutarate dehydrogenases (E. coli and P. putida YdiJ; SF119), the GlcE FAD-binding subunit of the heteromeric GlcDEF glycolate oxidase/dehydrogenase (SF103), and vanillyl-alcohol oxidase/p-cresol methylhydroxylase-like flavoenzymes acting on phenolic alcohols (SF114).

Metal-dependent epimerases interconverting ribulose 5-phosphate and xylulose 5-phosphate in the non-oxidative pentose phosphate pathway and the Calvin cycle (S. cerevisiae RPE1, S. pombe SPAC31G5.05c, human RPE, bacterial Rpe). Salmonella LsrE is an RPE-related paralog in an autoinducer-2 operon.

PLP-dependent fold-type I aminotransferases that interconvert L-alanine plus 2-oxoglutarate with pyruvate plus L-glutamate (EC 2.6.1.2). The family holds the fungal mitochondrial enzymes (S. cerevisiae ALT1 and its paralogue ALT2, S. pombe alt1) together with plant mitochondrial AlaATs in SF29, the vertebrate cytosolic GPT (SF308) and mitochondrial GPT2 (SF311), and the plant peroxisomal glutamate:glyoxylate aminotransferases GGAT1/GGAT2 (SF472/SF373), which carry additional glyoxylate-transaminase activities.

Sigma adaptins are small subunits of heterotetrameric adaptor complexes involved in membrane cargo sorting. AP-1, AP-2, AP-3 and AP-4 complexes use related sigma subunits at different membrane compartments. Their shared structural role does not identify a single vesicle destination.

Triterpene cyclases that fold and cyclize 2,3-oxidosqualene (or squalene) into polycyclic scaffolds. Lanosterol synthase (S. cerevisiae ERG7, S. pombe erg7, human LSS) makes the first sterol. Plant subfamilies make beta-amyrin, lupeol, arabidiol and other triterpenes, and fungal members make meroterpenoid scaffolds. Schizosaccharomyces japonicus has a horizontally acquired squalene-hopene cyclase in the lanosterol synthase subfamily.

Class II glutamine amidotransferases with an N-terminal Ntn glutaminase domain and a C-terminal adenylating synthetase domain that convert L-aspartate, L-glutamine and ATP to L-asparagine, L-glutamate, AMP and diphosphate (EC 6.3.5.4). Members include the two redundant S. cerevisiae enzymes ASN1 and ASN2, S. pombe asn1, E. coli AsnB and the Arabidopsis ASN1-ASN3 (SF2, SF38, SF48), vertebrate ASNS (SF23, SF36) and other plant paralogues. A small number of bacterial beta-lactam synthetases sit in SF2.

The PLP-dependent P protein of the glycine cleavage system decarboxylates glycine and transfers the aminomethyl group to the lipoyl arm of the H protein. The family contains bacterial GcvP (single-chain, or split into GcvPA/GcvPB), S. cerevisiae GCV2, S. pombe gcv2, plant GDCSP and animal GLDC.

The NADH-oxidising flavoprotein of the proton-pumping NADH:quinone oxidoreductases: bacterial NuoF (Nqo1 in Paracoccus) and mitochondrial NDUFV1. It sits at the matrix-facing tip of the peripheral arm, binds one non-covalently bound FMN and one [4Fe-4S] cluster (N3), and is where the whole enzyme begins: NADH docks on a glycine-rich loop, transfers a hydride to FMN, and the reduced flavin passes electrons one at a time to N3 and onward down the iron-sulfur wire to the quinone chamber built by the 49 kDa subunit family (PANTHER:PTHR11993). The reduced flavin is also the principal site at which complex I leaks electrons to oxygen, so this subunit carries the enzyme's superoxide chemistry as well as its productive chemistry. The family is strikingly uniform: in the fetched slice, alphaproteobacterial, actinobacterial, fungal, plant, amoebozoan and animal members all carry the same four N3 cysteine ligands and the same NADH-binding glycine loop, and there is no organellar or photosynthetic branch - the plastid NDH complex has no counterpart of this subunit at all, which is precisely why that complex is reduced by ferredoxin rather than by NADH.

NTPDase/apyrase-related enzymes hydrolyze nucleoside di- and triphosphates. Members operate extracellularly or in secretory compartments, with different preferences for ATP, ADP, UDP, GDP and other nucleotides. These differences connect the family to either extracellular nucleotide signaling or organellar glycosylation and nucleotide metabolism.

Signal transducers and activators of transcription (STATs) are latent cytoplasmic transcription factors that are activated by tyrosine phosphorylation, dimerize through reciprocal SH2-phosphotyrosine contacts, move to the nucleus and bind specific promoter elements. The family core is a DNA-binding domain with an immunoglobulin-like fold, a helical linker and an SH2 domain. Metazoan STATs add an N-terminal oligomerization domain and a C-terminal transactivation domain; Dictyostelium STATs lack both and C. elegans STA-1 lacks the N-terminal domain. In Bilateria with JAK kinases (vertebrates, Drosophila Stat92E/Hopscotch) STATs are the transcriptional arm of receptor-JAK-STAT signalling. Vertebrates have seven paralogs from whole-genome and later duplications, each tied to particular cytokine and hormone receptors: STAT1 and STAT2 for interferons (with IRF9 forming ISGF3), STAT3 for IL-6-family cytokines, leptin and growth factors, STAT4 for IL-12, STAT5A/STAT5B for IL-2-family cytokines, growth hormone and prolactin, and STAT6 for IL-4/IL-13. STATs are older than JAK: the four Dictyostelium STATs are activated through serpentine receptors and tyrosine kinase-like kinases, and the two C. elegans STATs act without JAK in immunity and development (STA-2 in the epidermis via SNF-12 and p38 MAPK, STA-1 in antiviral repression via SID-3). Plants have STAT-type linker-SH2 proteins (Arabidopsis SHA and SHB) that lack the STAT DNA-binding domain and whose function is unknown.

Fold-type I PLP enzymes of sulfur amino acid metabolism. Cystathionine gamma-lyase (S. cerevisiae CYS3, human CTH) cleaves cystathionine to cysteine in reverse transsulfuration. Cystathionine beta-lyase (S. cerevisiae STR3, S. pombe cbl1) releases homocysteine in forward transsulfuration. Cystathionine gamma-synthase (MetB) makes cystathionine from O-acylhomoserine and cysteine. Other members include O-succinylhomoserine sulfhydrylase (MetZ) and methionine gamma-lyase.

NADP-dependent 6-phosphogluconate dehydrogenases oxidatively decarboxylate 6-phosphogluconate to ribulose 5-phosphate, the third step of the oxidative pentose phosphate pathway. The family contains bacterial Gnd, S. cerevisiae GND1/GND2, S. pombe SPBC660.16, Candida GND1 and human PGD.

SLC26/SulP proteins share a membrane transport fold and commonly a STAS domain. Members transport different anions with different coupling modes; the family also includes the specialized mammalian prestin motor.

The beta subunit of succinyl-CoA synthetase carries the ATP-grasp nucleotide site and the succinate site, and sets ADP or GDP specificity. PANTHER roots the family at LUCA (PTN000212531). Bacteria and archaea have one beta subunit (SucC). The eukaryotic beta subunit duplicated once, at the root of eukaryotes (PTN000212530). One daughter clade (PTN008330414, the A-type lineage) contains animal SUCLA2, the fungal beta subunits (S. cerevisiae LSC2, S. pombe SPCC1620.08) and one Dictyostelium gene. The other (PTN002483419) contains animal and Dictyostelium SUCLG2 and, in the PANTHER tree, the beta subunits of plants, stramenopiles and excavates. GDP specificity is a derived state inside the second clade, in the animal, choanoflagellate and Dictyostelium branch (PTN000929335), marked by Gln at position 20 of the mature subunit; plant, stramenopile and excavate subunits keep the ancestral residue and are ADP-forming. Animals, choanoflagellates and Dictyostelium kept both copies and fungi kept only the A-type copy. Two points are robust across the PANTHER tree and independent distance and maximum-likelihood trees: the fungal subunits group with animal SUCLA2, and the Gln-carrying subunits of animals, a choanoflagellate and Dictyostelium form one clade. Which copy the plant, stramenopile and excavate subunits descend from is not resolved. The InterPro member list also places ATP-citrate synthase subunits, malate-CoA ligase beta and sulfoacetate-CoA ligase beta in the family.

Pyruvate kinases transfer the phosphoryl group of phosphoenolpyruvate to ADP, giving pyruvate and ATP in the final, essentially irreversible step of glycolysis. The family covers the bacterial PykF- and PykA-type enzymes, the fungal enzymes (S. cerevisiae CDC19 and PYK2, S. pombe pyk1), the vertebrate PKM and PKLR isozymes, and the cytosolic and plastidial pyruvate kinases of plants. Allosteric control differs between isozymes: for example, yeast CDC19 is activated by fructose 1,6-bisphosphate and PYK2 is not. The catalytic reaction is shared.

Homodimeric NADP-dependent isocitrate dehydrogenases make 2-oxoglutarate and NADPH. S. cerevisiae has mitochondrial IDP1, cytosolic IDP2 and peroxisomal IDP3, which supplies NADPH for beta-oxidation of unsaturated fatty acids. Animals have cytosolic/peroxisomal IDH1 and mitochondrial IDH2. They are not the NAD-dependent TCA-cycle IDH.

Voltage-gated calcium-channel beta subunits are cytosolic auxiliary proteins that regulate channel assembly, trafficking and gating through interaction with pore-forming alpha1 subunits. Their SH3/guanylate-kinase-like architecture supports protein interactions. It does not create a calcium-conducting pore or establish guanylate-kinase catalysis.

Branched-chain amino-acid aminotransferases reversibly exchange amino groups between branched-chain amino acids and their ketoacids using pyridoxal phosphate. Cytosolic, mitochondrial and microbial members retain related chemistry while serving different metabolic directions and compartments.

Beta-decarboxylating dehydrogenases oxidize a 2-hydroxy acid and decarboxylate it. The family contains the subunits of mitochondrial NAD-dependent isocitrate dehydrogenase (S. cerevisiae catalytic IDH2 and regulatory IDH1, S. pombe idh2/idh1, human IDH3A/B/G), homoisocitrate dehydrogenase of fungal lysine synthesis (LYS12, lys12), and archaeal and bacterial IPMDH-like or IDH enzymes.

GTP-dependent adenylosuccinate synthetases condense IMP with aspartate, the first step from IMP to AMP. The family contains bacterial and phage PurA, S. cerevisiae ADE12, plant plastid PURA, and animal ADSS1 (muscle) and ADSS2.

This membrane oxidoreductase grouping includes cholesterol hydroxylases, sterol desaturases and other lipid-modifying enzymes. CH25H converts cholesterol to 25-hydroxycholesterol, a reaction distinct from sterol C4 demethylation or introduction of a sterol double bond. Related metal-dependent architectures do not make these reactions interchangeable.

PLP-dependent fold-type I (subfamily Ia) aminotransferases. The eukaryotic members are the aspartate aminotransferases (L-aspartate:2-oxoglutarate transaminases) that interconvert aspartate + 2-oxoglutarate and oxaloacetate + glutamate. These include the cytosolic isozymes (S. cerevisiae AAT2, S. pombe caa1, human GOT1) and the mitochondrial isozymes (S. cerevisiae AAT1, S. pombe SPBC725.01/maa1, human GOT2), which together run the malate-aspartate shuttle, plus plant mitochondrial, cytosolic and plastid isozymes. The bacterial members are E. coli AspC, a broad aspartate/aromatic aminotransferase, and the TyrB aromatic-amino-acid aminotransferases that make phenylalanine and tyrosine. A few fungal secondary-metabolism aminotransferases are also classified here.

PTHR11889 contains the Hedgehog ligands, the secreted signals that initiate Hedgehog pathway activity across animals. Every member is made as a precursor with two parts: an N-terminal signaling domain that carries all the known receptor-binding activity, and a C-terminal Hint/Hog domain that is not a signal at all but an enzyme, cleaving the precursor and transferring cholesterol onto the new C-terminus of the signaling domain in a single reaction cycle. An acyltransferase outside this family then palmitoylates the new N-terminus, and the dually lipidated product engages Patched on the receiving cell. The family is functionally tight in a way that most PANTHER families are not: the same precursor architecture, the same self-processing chemistry, and the same receptor target run from the single Drosophila hh gene to the vertebrate SHH, IHH and DHH paralogs. What varies between members is not the molecular function but the range and potency of signaling, and the vertebrate paralogs differ substantially on both.

Enolases are Mg2+-dependent dimeric enzymes that dehydrate 2-phospho-D-glycerate to phosphoenolpyruvate in glycolysis and catalyse the reverse hydration in gluconeogenesis. The family is one of the most conserved in central metabolism and contains the glycolytic enolases of bacteria, archaea and eukaryotes. In S. cerevisiae it includes the two abundant glycolytic isozymes ENO1 and ENO2 and the three near-identical subtelomeric ERR1/ERR2/ERR3 proteins. In S. pombe it includes eno101 and eno102. In vertebrates it includes the alpha (ENO1), gamma (ENO2, neuronal), beta (ENO3, muscle) and sperm ENO4 isozymes, and in plants a plastid-targeted enolase beside the cytosolic ones.

Trimeric purine nucleoside phosphorylases phosphorolyse inosine, guanosine and their 2'-deoxy forms to the base and (deoxy)ribose 1-phosphate in purine salvage. S. cerevisiae PNP1 also cleaves nicotinamide riboside in NAD salvage. The family contains S. cerevisiae PNP1, S. pombe SPAC1805.16c and human PNP.

Amidophosphoribosyltransferase (glutamine phosphoribosylpyrophosphate amidotransferase, PurF, EC 2.4.2.14) catalyses the committed first step of de novo purine synthesis: PRPP and glutamine are converted to 5-phosphoribosylamine, glutamate and pyrophosphate. The enzyme combines an N-terminal class II (Ntn) glutamine amidotransferase domain, whose N-terminal cysteine is exposed by removal of a propeptide, with a C-terminal type I phosphoribosyltransferase domain. It is feedback-inhibited by purine nucleotides. Members include bacterial PurF (E. coli, B. subtilis, Pseudomonas), fungal ADE4 (S. cerevisiae, S. pombe), animal PPAT, and the plastid isozymes of plants. A few reviewed members carry only the glutamine-amidotransferase domain (Rhizobium GlxB, Methanothermobacter MTH_191). There is also a fungal PurF paralog, FrzK, in an alkaloid biosynthetic gene cluster.

Molybdo-flavo hydroxylases and their molybdopterin-binding subunits. The family unites the fused eukaryotic xanthine dehydrogenases and aldehyde oxidases (in PANTHER's own classification) with the separate molybdenum-cofactor subunits of split bacterial enzymes: XdhB of two-subunit XdhAB xanthine dehydrogenases (Rhodobacter capsulatus, Pseudomonas), E. coli XdhA and XdhD, PaoC aldehyde oxidoreductase, CoxL/CutL carbon monoxide dehydrogenases, caffeine, nicotine, nicotinate, uracil/thymine and 4-hydroxybenzoyl-CoA reductase large subunits, and B. subtilis PucD. All carry the Mo-molybdopterin active site where the substrate is hydroxylated; the substrate, the electron acceptor and the partner subunits differ widely between branches.

IMP dehydrogenases oxidize IMP to XMP, the rate-limiting step of GTP synthesis; they are the target of mycophenolic acid. The family contains bacterial GuaB, the S. cerevisiae IMD2-4 paralogs, human IMPDH1/2 and plant IMPDH. It also contains GMP reductases, which reduce GMP back to IMP.

The iron-sulphur subunit of complex II (SdhB/SDH2/SDHB) carries [2Fe-2S], [4Fe-4S] and [3Fe-4S] clusters that pass electrons from the flavoprotein to the membrane-bound ubiquinone site. The family contains bacterial SdhB and FrdB, S. cerevisiae SDH2, S. pombe sdh2 and human SDHB.

Glutamine amidotransferases that aminate XMP to GMP with ammonia generated by their glutaminase domain, the last step of de novo GMP synthesis (bacterial GuaA, S. cerevisiae GUA1, human GMPS).

2,3-Bisphosphoglycerate-dependent phosphoglycerate mutases interconvert 3- and 2-phosphoglycerate through a phosphohistidine intermediate, the eighth step of glycolysis (bacterial GpmA, S. cerevisiae GPM1, S. pombe gpm1, human PGAM1/PGAM2). Bisphosphoglycerate mutase (BPGM) of erythrocytes instead makes 2,3-BPG. The S. cerevisiae paralogs GPM2 and GPM3 are not functional phosphoglycerate mutases.

Type A ribose-5-phosphate isomerases interconvert ribose 5-phosphate and ribulose 5-phosphate in the non-oxidative pentose phosphate pathway (bacterial RpiA, S. cerevisiae RKI1, S. pombe rki1, human RPIA).

Glyoxalase-II-related metallohydrolases include hydroxyacylglutathione hydrolases and divergent PNKD proteins. Classical glyoxalase II hydrolyzes S-lactoylglutathione in methylglyoxal detoxification. Human PNKD-L shows very low turnover of this substrate and fails to restore its metabolism in a fly HAGH-null background, establishing a functional boundary despite the related fold.

PANTHER tree that joins two functionally distinct groups of flavoproteins. The larger group is the glutamate synthase (GOGAT) catalytic chain: the bacterial NADPH-GOGAT large chain GltB (E. coli, P. putida KT2440), the Gram-positive and alpha-proteobacterial large chains (B. subtilis GltA, Azospirillum GltB) and the plant ferredoxin-dependent GOGATs. These proteins carry an N-terminal Ntn-type glutamine amidotransferase linked by an ammonia tunnel to an FMN/[3Fe-4S] synthase domain that reductively aminates 2-oxoglutarate. In the PANTHER classification files the full-length eukaryotic NADH-GOGATs (yeast GLT1, fission yeast glt1) also sit in this tree, although UniProt's HMM assignment places them in PTHR43100. The second group is the mitochondrial NADPH:adrenodoxin oxidoreductase clade (subfamily SF91, FDXR / Arh1), which reduces adrenodoxin/ferredoxin for mitochondrial P450 and coenzyme Q chemistry and has no amidotransferase activity.

The reviewed inventory includes enoyl-CoA hydratases, enoyl-CoA isomerases, methylglutaconyl-CoA hydratase and ethylmalonyl-CoA decarboxylase. Bacillus subtilis 168 FadB/YsiB P94549 is a verified SF175 member with directly measured recombinant crotonyl-CoA hydration. The common fold and family label do not determine the reaction or native pathway for every member.

Class I hexose-1-phosphate uridylyltransferases exchange the UMP of UDP-glucose onto galactose 1-phosphate by a ping-pong mechanism, the central step of the Leloir pathway (bacterial GalT, S. cerevisiae GAL7, S. pombe gal7, human GALT, whose loss causes classic galactosemia).

UDP-sugar pyrophosphorylase relatives activate sugar phosphates with UTP to supply nucleotide-sugar donors. UAP1-type proteins act on N-acetylhexosamine phosphates, while other branches use different sugars. The identity and stereochemistry of the sugar phosphate determine the biochemical annotation.

Eukaryotic family of barrel-shaped homotrimeric cytokines and keto-enol tautomerases/isomerases comprising macrophage migration inhibitory factor (MIF, PTHR11954:SF6) and its functional paralog D-dopachrome tautomerase / D-dopachrome decarboxylase (DDT / MIF-2, PTHR11954:SF22), together with the primate duplicate DDTL (PTHR11954:SF39) and nematode MIF-like proteins (mif-2, mif-3). Members share a conserved 4-oxalocrotonate tautomerase-like beta-alpha-beta fold that assembles into a three-fold symmetric homotrimer with three catalytic pockets at the subunit interfaces, each centered on an invariant catalytic N-terminal proline (Pro-2 after initiator Met-1 cleavage) that catalyzes phenylpyruvate tautomerization and D-dopachrome isomerization. In vertebrates and bilaterians, secreted MIF and DDT function as high-affinity agonistic cytokine ligands for the cell-surface receptor CD74 (the MHC class II invariant chain), recruiting the signaling co-receptor CD44 to activate Src tyrosine kinases and the sustained ERK1/2 MAP kinase cascade.

Methionine adenosyltransferases make S-adenosylmethionine from methionine and ATP. The family contains bacterial MetK, S. cerevisiae SAM1/SAM2, S. pombe sam1, human MAT1A (liver) and MAT2A, and plant SAMS isozymes.

NADPH oxidase and ferric-reductase relatives transfer electrons across membranes through flavin and heme cofactors. NOX/DUOX branches generate reactive oxygen species, whereas ferric reductases reduce extracellular or organellar metal substrates. DUOX proteins additionally carry extracellular peroxidase-like regions and calcium-responsive regulatory elements.

FAD-dependent glycerol-3-phosphate dehydrogenases oxidize glycerol 3-phosphate to dihydroxyacetone phosphate and pass electrons to quinone. Aerobic bacterial GlpD, S. cerevisiae GUT2, S. pombe gut2 and human GPD2 act on the outer face of the respiratory membrane (the glycerol phosphate shuttle in eukaryotes). The family also contains anaerobic GlpA and the H2O2-producing glycerol-3-phosphate oxidases (GlpO).

Pyridoxal 5'-phosphate-dependent fold-type I class-III aminotransferases that transfer a terminal (omega or delta) amino group to 2-oxoglutarate. The family groups several distinct enzymes with different amino donors: ornithine delta-aminotransferase (OAT; yeast CAR2, fission yeast car2, human OAT, plant delta-OAT, Bacillus RocD), the anabolic N-acetylornithine aminotransferases of arginine biosynthesis (bacterial ArgD, fungal mitochondrial ARG8/arg1, plant WIN1), the catabolic N-succinylornithine transaminases of the arginine succinyltransferase pathway (E. coli AstC, Pseudomonas AruC), E. coli PatA putrescine aminotransferase, and 4-aminobutyrate / 5-aminovalerate aminotransferases such as PuuE and DavT. The shared chemistry is PLP-dependent omega-transamination; the amino donor, and therefore the pathway, is set by subfamily.

The large "49 kDa" subunit that forms the quinone-reduction chamber of every proton-pumping NADH:quinone oxidoreductase and of the plastid NDH complex. Members are bacterial NuoD (often fused to NuoC as a single NuoCD chain), mitochondrial NDUFS2 and its organelle-encoded plant counterpart NAD7, and the plastid-encoded NdhH of the thylakoid NAD(P)H dehydrogenase complex. The subunit descends from the large subunit of [NiFe] hydrogenase and retains that fold, but the metal site is vestigial: no structure of bacterial, mitochondrial or plastid complex I places an iron-sulfur cluster on it, and the terminal N2 cluster that delivers electrons into the quinone site is held by the neighbouring NuoB/NDUFS7 subunit instead. What the subunit does contribute, family-wide, is the amphipathic quinone channel and the invariant His/Tyr pair at its mouth that hydrogen-bonds the quinone headgroup. The identity of that quinone is where the family divides: ubiquinone or menaquinone in the respiratory members, plastoquinone in the plastid NdhH clade, whose complex is reduced by ferredoxin rather than by NADH and runs cyclic electron flow around photosystem I rather than respiration.

Homologous subunits of respiratory complex I and chloroplast NDH: NuoB / mitochondrial NDUFS7 / plastid NdhK. Respiratory complexes receive electrons from NADH, whereas the chloroplast NDH complex lacks the NADH-oxidizing module and uses reduced ferredoxin to reduce plastoquinone. Coupled proton translocation is conserved. The chloroplast complex contributes to cyclic photosynthetic ATP production and has evidence for chlororespiratory participation; chloroplast localization does not by itself negate respiratory process terms.

Isoprenyl diphosphate synthases that extend allylic diphosphates with IPP to a set chain length. The family contains GGPP synthases (S. cerevisiae BTS1, human GGPS1), the long-chain polyprenyl diphosphate synthases that make the ubiquinone tail (S. cerevisiae COQ1, hexaprenyl; S. pombe dps1/dlp1 and human PDSS1/PDSS2 heterodimers, decaprenyl; bacterial IspB, octaprenyl), and fungal secondary-metabolite prenyltransferases.

Secreted chemotactic cytokines (chemokines) sharing the conserved intercrine alpha/beta fold (a three-stranded antiparallel beta-sheet overlain by a C-terminal alpha-helix stabilized by one or two disulfide bonds). Family members bind class A seven-transmembrane G-protein-coupled chemokine receptors (primarily Gi/o-coupled CXCR, CCR, XCR, and CX3CR receptors) and glycosaminoglycans on endothelial and extracellular matrix surfaces to establish haptotactic and chemotactic gradients that direct leukocyte trafficking, degranulation, and inflammatory signaling. Major vertebrate clades within this family include ELR+ CXC chemokines (such as CXCL8/IL-8 and CXCL1-3/5-7, which signal through CXCR1 and CXCR2 on neutrophils), ELR- CXC chemokines (such as CXCL9/10/11 via CXCR3 and CXCL12 via CXCR4), and CC chemokines (such as CCL2, CCL3, CCL4, CCL5, and eotaxins via CCR receptors).

Nicotinamide/nicotinate mononucleotide adenylyltransferases make NAD or deamido-NAD from NMN or NaMN and ATP, the step shared by all NAD synthesis routes. The family contains S. cerevisiae NMA1/NMA2, S. pombe SPAC806.06c, Drosophila Nmnat and human NMNAT1 (nuclear), NMNAT2 (Golgi/axonal) and NMNAT3 (mitochondrial).

Allantoicases hydrolyse allantoate to ureidoglycolate and urea in the uric acid degradation pathway of bacteria, fungi (S. cerevisiae DAL2, S. pombe SPAC1F7.09c) and non-amniote vertebrates. Amniotes lost the pathway, and human ALLC, though retained and transcribed, has no allantoicase activity.

CNNM/ACDP proteins contain a membrane region and cytosolic regulatory architecture associated with metal-ion homeostasis. Mammalian CNNMs and fungal or plant homologs differ in membrane destination and physiological context.

The CD2/SLAM family comprises hematopoietic cell-surface glycoproteins with a membrane-distal IgSF V-set domain and a membrane-proximal C2-set domain. It splits into two functional classes. The SLAM-related receptors (SLAMF1, LY9, CD84, SLAMF6, SLAMF7 and 2B4/CD244) are type I transmembrane receptors whose cytoplasmic immunoreceptor tyrosine-based switch motifs recruit SAP/EAT-2 adaptors; most are homophilic, while 2B4 binds CD48. CD2 is a transmembrane adhesion and costimulatory receptor. The ligand class has no signaling tail: CD48 is GPI-anchored and serves as the ligand of 2B4 (and of CD2 in rodents), and CD58/LFA-3 is the human CD2 ligand. SLAMF8, SLAMF9 and the neuronal VSTM5 are more distant members with less defined functions.

VPS10-domain sorting receptors (IPR006581 / IPR050310) across Eukaryota, including fungal Vps10/Pep1 vacuolar hydrolase receptors (SF27), metazoan sortilin (SORT1, SF23), mosaic sortilin-related receptor (SORL1/SORLA, SF27), and vertebrate SorCS1-3 receptors (SF8, SF9, SF10). All family members are single-pass type I transmembrane glycoproteins bearing an N-terminal 10-bladed beta-propeller VPS10 luminal ligand-binding domain and a short cytosolic tail containing sorting motifs recognized by retromer (VPS26-VPS35-VPS29) and GGA/AP-1 clathrin adaptors, enabling iterative cargo-sorting cycles between the trans-Golgi network (TGN), endosomes, and the cell surface.

Alg14 is the ER membrane-anchored subunit of the Alg13-Alg14 UDP-GlcNAc transferase. It recruits the cytosolic catalytic subunit Alg13 to the ER membrane for the second step of lipid-linked oligosaccharide assembly (S. cerevisiae ALG14, S. pombe alg14, human ALG14).

Lipins are Mg2+-dependent phosphatidate phosphatases (PAP1) that dephosphorylate phosphatidic acid to diacylglycerol on the ER and nuclear membrane, directing glycerolipid flux to triacylglycerol and phospholipid synthesis. They are regulated by phosphorylation and membrane recruitment. The family contains S. cerevisiae PAH1, S. pombe ned1, plant PAH1/2 and human LPIN1-3; mammalian lipins also act as transcriptional coactivators.

ChaC-family enzymes cleave glutathione into 5-oxoproline and cysteinylglycine, a cytosolic route of glutathione degradation. The family contains S. cerevisiae GCG1, S. pombe ggg1, human CHAC1 (ER-stress induced) and CHAC2, and plant GGCT2.

The family is defined by the DUF71 adenine nucleotide alpha hydrolase-like (PP-loop ATP pyrophosphatase) domain. Its characterized members are Dph6, the diphthine-ammonia ligase (diphthamide synthetase, EC 6.3.1.14) that completes diphthamide on translation elongation factor 2. Using ATP and free ammonium (not glutamine), it amidates the carboxylate of diphthine, releasing AMP and diphosphate. Yeast YLR143W/Dph6 was identified by chemogenomic cofitness and reconstituted in vitro, and the human ortholog ATPBD4/DPH6 fully complements the yeast deletion. Yeast Dph6 carries a long C-terminal extension that the human protein lacks. Dph6 homologs occur in eukaryotes and archaea, the two domains whose EF2 carries diphthamide. The PANTHER family also contains many bacterial DUF71 proteins, annotated only as PP-loop or ATP-binding proteins. Bacteria make no diphthamide, so these have an unknown function.

FCP/SCP-like phosphatase-domain proteins in this family serve distinct cellular roles. CTD small phosphatases such as CTDSP2 dephosphorylate protein substrates associated with transcriptional regulation, whereas TIM50-family proteins participate in mitochondrial precursor import. Shared phosphatase-like architecture does not make all members mitochondrial translocase subunits.

Sfp-type phosphopantetheinyl transferases attach the 4'-phosphopantetheine arm of CoA to carrier domains. In fungi, LYS5 (S. cerevisiae) and lys7 (S. pombe) activate alpha-aminoadipate reductase (LYS2) for lysine synthesis. Human AASDHPPT activates the acyl carrier proteins of cytosolic fatty acid synthase and of mitochondria.

Polytopic membrane proteins of the PQ-loop type. The characterized member, mammalian MPDU1 (Lec35, SL15), is an endoplasmic-reticulum membrane protein required for use of the lipid-linked donors mannose-P-dolichol and glucose-P-dolichol by the lumenal glycosyltransferases of LLO, GPI and C-mannose synthesis. It is not itself a glycosyltransferase and is thought to control the presentation or orientation of the donor in the membrane; MPDU1 mutations cause MPDU1-CDG (CDG-If). The family also contains a vertebrate/insect paralog group, SLC66A3 (PQLC3), whose function is not established, and plant MPDU1 homologs.

Arrestin-fold cargo-adaptor subunits of endosomal retrieval complexes across Eukaryota, encompassing the retromer cargo-selective complex (CSC) subunits VPS26A and VPS26B (and single-copy invertebrate/fungal Vps26/Pep8 orthologs) as well as the retriever complex subunit VPS26C (DSCR3). All characterized members adopt a bilobed beta-sandwich arrestin-like fold that docks onto the N-terminal region of an alpha-solenoid scaffold (VPS35 in retromer or VPS35L in retriever) and cooperates with sorting nexins (SNX3, SNX27, or SNX17) to recognize cytosolic sorting motifs on transmembrane cargos for endosomal retrieval and recycling.

This membrane-protein grouping includes fly Headbutt and Rolling stone in distinct subfamilies, alongside plant membrane-protein descriptors. Rolling stone is required for myoblast fusion; no common transport reaction or lipid substrate is established across the grouping.

Type II pantothenate kinases (PanK, EC 2.7.1.33) catalyze the ATP-dependent phosphorylation of (R)-pantothenate to 4'-phosphopantothenate, the first and rate-limiting step of coenzyme A synthesis. They have an actin-like ASKHA fold, and CoA and acyl-CoAs feedback-inhibit them. The family covers the human PANK1-3 isoforms, S. cerevisiae Cab1, S. pombe ptk1, plant PANKs and the staphylococcal type II CoaW enzymes. It also contains two groups that do not phosphorylate pantothenate. The first is PANK4, a PanK domain fused to a C-terminal DUF89 (ARMT1-like) metal-dependent phosphatase domain that dephosphorylates 4'-phosphopantetheine. In amniotes, including human, the PanK domain of PANK4 has lost two catalytic residues and is inactive. The second is a group of plant proteins made only of the DUF89 domain (for example Arabidopsis At2g17340, a damage-control phosphatase).

A composite PANTHER family that groups two unrelated kinds of protein. Most subfamilies are cornichon proteins: small multi-pass ER membrane proteins (Pfam Cornichon, PF03311) that act as COPII cargo receptors (S. cerevisiae Erv14/Erv15, Drosophila cni, plant CNIHs). Vertebrate CNIH2/CNIH3 are also AMPA receptor auxiliary subunits. Subfamily SF2 holds the eukaryotic monofunctional phosphopantothenate--cysteine ligases (PPCS, EC 6.3.2.5/6.3.2.51): human PPCS, S. cerevisiae Cab2, S. pombe ppc1 and Arabidopsis PPCS1/PPCS2. These are soluble DFP-domain enzymes (Pfam PF04127) that condense 4'-phosphopantothenate with L-cysteine, the second step of coenzyme A synthesis. PANTHER's own InterPro description names the family Cornichon/Phosphopantothenate--cysteine ligase.

Calcium-dependent nucleoside hydrolases cleave the N-glycosidic bond of ribonucleosides. Fungal URH1 (S. cerevisiae URH1, S. pombe SPAC17G8.02 and SPBC1683.06c) prefers uridine and also hydrolyses nicotinamide riboside for NAD salvage. Bacterial RihA/RihC and plant URH1/2 vary in purine or pyrimidine preference.

ABT1/Esf2 proteins are nuclear interaction factors linked to RNA production and ribosome biogenesis. Yeast Esf2 binds pre-rRNA, participates in U3/90S small-subunit biogenesis and stimulates the helicase Dbp8. The conserved molecular role is better defined by these RNA-processing interactions than by a generic transcription-associated name.

ER membrane acyl-CoA-dependent acyltransferases of the DGAT2 family. DGAT2 (human DGAT2, S. cerevisiae DGA1, S. pombe dga1) makes triacylglycerol from diacylglycerol. Related subfamilies acylate monoacylglycerol (MOGAT1-3) or wax alcohols (AWAT1/2).

Importin-beta-like receptors bind selected cargoes and mediate nucleocytoplasmic transport. This family includes importin-13 and transportin-3/Mtr10-related branches, with different cargo preferences and potentially different transport directions for particular substrates. Ran-dependent cargo exchange couples transport to the nuclear compartment.

Soluble inositol polyphosphate kinases with a PxxxDxKxG catalytic motif. Inositol polyphosphate multikinase (S. cerevisiae ARG82, S. pombe arg82, human IPMK) makes IP4 and IP5 from IP3. IP6 kinases (S. cerevisiae KCS1, S. pombe SPCC970.08, human IP6K1-3) make the 5-diphosphoinositol pyrophosphate 5-IP7. Animal ITPKA-C phosphorylate IP3 at the 3-position.

ER-lumenal Dol-P-Glc-dependent glucosyltransferases that add the first two glucoses to the lipid-linked oligosaccharide: ALG6 (SF1) adds alpha-1,3-glucose to Man9GlcNAc2-PP-Dol, and ALG8 (SF2) adds the second alpha-1,3-glucose (S. cerevisiae, S. pombe and human orthologs).

The Neuralized family is defined by the Neuralized homology repeat (NHR; Pfam PF07177), a beta-sandwich substrate-binding module. Drosophila Neuralized (neur), the founding member, has two NHRs and a C-terminal RING finger. It is a RING E3 ubiquitin ligase that binds and ubiquitinates Delta and promotes Delta endocytosis in the signal-sending cell, positively regulating Notch signalling. Vertebrates have several paralogues with different domain plans and functions. NEURL1 and NEURL1B (Neur1/Neur2) keep the NHR-RING plan. They can ubiquitinate Notch ligands (Neurl1 acts on Jagged1; Neur2 acts on Delta together with Mib1), but mouse Neur1; Neur2 double mutants are viable and grossly normal. NEURL3 (LINCR) is a short NHR-RING E3 with no established Notch role. NEURL2 (Ozz) has one NHR and a SOCS box but no RING. It is the substrate adaptor of a muscle Cullin-RING ligase that degrades membrane beta-catenin during myofibrillogenesis. NEURL4 has six NHRs and no RING. It is a daughter-centriole protein that restrains CP110 and prevents ectopic microtubule-organising centres.

EFR3 proteins anchor phosphatidylinositol-4-kinase-associated assemblies at the plasma membrane. Their conserved role is recruitment and organization of a lipid-kinase complex, allowing membrane phosphoinositide synthesis to occur at the correct location. EFR3A and EFR3B represent closely related mammalian branches.

NOL4-family proteins are nuclear interaction proteins with isoform-dependent regulatory activities demonstrated in mammals. Mouse NOL4 splice variants bind the Mlr1/Mlr2 transcription factors and alter their transcriptional output; the conserved molecular role of the divergent fly CG46301 product remains unresolved.

FAM20 proteins share a secretory-pathway kinase-like architecture but diverge in catalytic output. FAM20B phosphorylates xylose in the glycosaminoglycan linkage region; FAM20C phosphorylates secreted proteins; FAM20A is a regulatory pseudokinase that supports FAM20C function. Sugar phosphorylation and protein phosphorylation are distinct activities.

SDHAF2/Sdh5/SdhE proteins promote maturation of the succinate-dehydrogenase flavoprotein, particularly covalent flavinylation. They help establish a catalytically competent flavoprotein rather than serving as the respiratory substrate-oxidizing enzyme. The same assembly principle spans mitochondrial and bacterial systems.

This family includes JMJD4, JMJD6, JMJD8 and plant JMJ20/JMJ22-like proteins. JmjC architecture unites the group but does not establish a common substrate, chromatin role or developmental pathway.

ENY2/Sus1 proteins couple transcription and nuclear mRNA export through membership in SAGA and TREX-2. Within SAGA they support the histone H2B deubiquitination module; within TREX-2 they help connect export machinery to the nuclear pore. These are small noncatalytic complex subunits, so SAGA membership does not confer intrinsic histone acetyltransferase or deubiquitinase activity.

TLC-domain ER membrane ceramide synthases N-acylate sphinganine and sphingosine with acyl-CoA. Fungal LAG1/LAC1 (S. cerevisiae), lag1/lac1 (S. pombe) and the six mammalian CERS paralogs differ in acyl-chain preference (CERS1 C18, CERS2 C22-C24, CERS3 very-long-chain).

This family contains glycerol-3-phosphate acyltransferases and dihydroxyacetone phosphate acyltransferases, which initiate different branches of glycerolipid synthesis. Human GPAM/GPAT1 transfers an acyl group to glycerol-3-phosphate at the mitochondrial outer membrane. Its experimentally determined membrane association uses an amphipathic surface rather than the transmembrane topology formerly proposed.

CPEB proteins bind regulatory elements in mRNA 3-prime untranslated regions and control translation through cytoplasmic polyadenylation and repression mechanisms. Their conserved RNA-binding region combines RNA recognition motifs with a zinc-binding domain. Orb and the CPEB paralogs have different mRNA targets and developmental deployments, while the shared activity is post-transcriptional regulation rather than transcription factor activity.

Phospholipase D (PLD)-superfamily phosphatidyltransferases that transfer the phosphatidyl group of CDP-diacylglycerol to a soluble alcohol acceptor. There are two characterized groups. Eukaryotic PGS1 (yeast PGS1/PEL1, S. pombe pgs1, human PGS1) is the mitochondrial phosphatidylglycerophosphate (PGP) synthase. It uses sn-glycerol 3-phosphate and catalyses the committed step of phosphatidylglycerol and cardiolipin synthesis. Type-I bacterial PssA (E. coli, H. influenzae, P. putida) is a peripheral-membrane phosphatidylserine synthase that uses L-serine. These enzymes are unrelated to the integral-membrane CDP-alcohol phosphatidyltransferases of PTHR14269, which include bacterial and plant PgsA, the type-II PS synthases and yeast CHO1.

PHRF1-related PHD/RING proteins include poorly characterized eukaryotic interaction proteins and a Komagataella micropexophagic-apparatus component catalogued as Atg36/Atg35. Shared zinc-binding domains do not establish identical ubiquitin-ligase substrates or a conserved autophagy-receptor mechanism.

NF-YA/Hap2 proteins form the sequence-recognition component of the heteromeric CCAAT-binding transcription factor. DNA binding and transcriptional regulation depend on assembly with the other NF-Y subunits. Fungal iron and oxidative-stress responses and plant developmental functions represent deployment of this conserved transcriptional machinery in different regulatory networks.

ALG3 adds the first ER-lumenal mannose (alpha-1,3) to Man5GlcNAc2-PP-Dol using Dol-P-Man, after the flippase step (S. cerevisiae ALG3, S. pombe alg3, human ALG3).

Pan-eukaryotic family of integral peroxisomal membrane proteins that drive peroxisome proliferation by the growth-and-division pathway: they deform and elongate the peroxisomal membrane and coordinate recruitment of the shared fission machinery (FIS1/MFF and the dynamin-related GTPase DRP1/DNM1L/Dnm1) to complete organelle division. The fetched reviewed slice spans fungi (S. cerevisiae PEX11/PMP27 and the divergent paralog PEX25, Candida boidinii PMP30A/B, S. pombe pex11), plants (Arabidopsis PEX11A-E, rice PEX11-1..5), amoebozoa (Dictyostelium pex11) and animals (mammalian PEX11A and PEX11B). Human PEX11B (the family's best-characterized mammalian member) is the constitutive driver of peroxisome fission: its overexpression alone induces peroxisome proliferation, its N-terminal domain mediates the homo-oligomerization required for membrane elongation, and it forms ternary complexes with FIS1 and DLP1. Note that human PEX11G is NOT in this family — the PANTHER member index places Q96HA9 in PTHR20990 — so the family's human members are PEX11A (SF22) and PEX11B (SF7) only.

GBA2 proteins hydrolyze glucosylceramide outside the lysosomal GBA pathway. Human isoform-expression experiments show strong activity and altered ceramide balance for isoform 1, whereas the other tested isoforms had activity near background. An assignment of the family therefore supports a glycosphingolipid-metabolism hypothesis but is insufficient to declare every alternative protein record catalytically active.

Small (about 150-220 aa), deeply conserved family of multi-pass ER membrane proteins comprising yeast Orm1/Orm2, plant ORM proteins, insect ORMDL and the three vertebrate paralogs ORMDL1/2/3. All characterized members are stoichiometric regulatory subunits of the serine palmitoyltransferase (SPT) complex, the first and rate-limiting enzyme of de novo sphingolipid biosynthesis, and act as its sphingolipid-responsive negative regulators: the ORMDL N-terminus occludes the SPT substrate entry tunnel, and ceramide binding stabilizes this inhibitory conformation, implementing a homeostatic negative feedback loop. The functional equivalence across the family is experimentally direct — human ORMDL3 rescues the yeast orm1/orm2 double mutant, and triple knockdown of ORMDL1/2/3 in HeLa cells raises ceramide about three-fold. Human ORMDL3 (17q21) is additionally the strongest replicated childhood-asthma GWAS locus, but its immune phenotypes are downstream of the conserved sphingolipid-regulatory job. The family is a textbook case where family-wide propagation of the SPT-complex and sphingolipid-homeostasis terms is safe.

Rpf2 proteins are conserved Brix-domain ribosome assembly factors. Together with Rrs1 and ribosomal proteins, they participate in incorporation and maturation of the large-subunit ribonucleoprotein particle. Their role is RNA binding and preribosome assembly rather than peptide synthesis or an intrinsic rRNA-processing nuclease reaction.

Bifunctional PPIP5K/Vip1 enzymes have an ATP-grasp kinase domain that pyrophosphorylates the 1-position of IP6 and 5-IP7 (making 1-IP7 and 1,5-IP8) and a C-terminal histidine-acid phosphatase-like domain that dephosphorylates them. The family contains S. cerevisiae VIP1, S. pombe asp1 and human PPIP5K1/2.

BadF/BadG/BcrA-type ATPase-fold kinases that phosphorylate N-acetylglucosamine to GlcNAc 6-phosphate, salvaging GlcNAc into the hexosamine pathway. Human NAGK also phosphorylates N-acetylmannosamine and muramyl dipeptide.

ER membrane di-iron fatty acid 2-hydroxylases with a cytochrome b5 domain hydroxylate the C2 of the ceramide N-acyl chain (fungi, S. cerevisiae SCS7 and S. pombe scs7; plants, FAH1/FAH2) or of free fatty acids (animal FA2H), producing 2-hydroxylated sphingolipids.

Palmitoylated, membrane-bound type II PI 4-kinases phosphorylate phosphatidylinositol to PI4P on endosomes, the trans-Golgi network and the plasma membrane (S. cerevisiae LSB6, S. pombe lsb6, animal PI4K2A/B). They are structurally unrelated to the type III PI4Ks of PTHR10048.

Alg13 is the cytosolic catalytic GT1 subunit of the Alg13-Alg14 UDP-GlcNAc transferase, which adds the second beta-1,4-GlcNAc to GlcNAc-PP-dolichol. Fungal ALG13 (S. pombe alg13) is a single-domain enzyme; vertebrate ALG13 (SF7) also carries an OTU deubiquitinase domain.

Di-iron membrane desaturases that introduce the 4,5-trans double bond into dihydroceramide to make ceramide (DEGS1, S. pombe dsd1). DEGS2 also hydroxylates C4, making phytoceramide. S. cerevisiae has no member: it makes phytoceramides with the unrelated hydroxylase SUR2.

APH-1 is the seven-transmembrane scaffold subunit of gamma-secretase. It assembles with nicastrin into an early subcomplex that then recruits presenilin and PEN-2, and it is needed for presenilin to accumulate and for the complex to be active. APH-1 was identified in a C. elegans screen for genes interacting with sel-12/presenilin and aph-2/nicastrin in Notch (GLP-1/LIN-12) signaling. RNAi against Drosophila aph-1 reduces gamma-secretase cleavage of Notch and APP. The family is found across eukaryotes. Vertebrates have duplicated it into APH1A and APH1B, and rodents have a further APH1B/APH1C duplication. Different APH-1 paralogs give gamma-secretase complexes with somewhat different substrate preferences and cleavage outcomes. Dictyostelium Aph1 is needed for gamma-secretase activity in an organism with no Notch.

Pan-eukaryotic family of C-terminal SUN-domain proteins. These are type II integral proteins of the inner nuclear membrane. Each has a nucleoplasmic N-terminal region that binds lamins or chromatin/telomere/centromere partners, a transmembrane segment, luminal coiled coils that trimerize, and a C-terminal SUN domain in the perinuclear space. The SUN domain binds the C-terminal KASH (or KASH-like) peptides of outer-nuclear-membrane proteins. The resulting SUN-KASH bridges (LINC complexes) span the nuclear envelope and couple the nucleoskeleton and chromosomes to cytoskeletal force. The family covers: (1) Vertebrate SUN1 (SF23) and SUN2 (SF22). These are ubiquitous somatic LINC anchors for nesprins in nuclear positioning, nucleokinesis and mechanotransduction. SUN1, and SUN2 in part, also pairs with KASH5 to tether meiotic telomeres. (2) An amniote testis-specific clade: SUN3 (SF24), SPAG4/SUN4 (SF16) and SUN5 (SF44). These form spermiogenesis-specific LINC complexes that shape the sperm head and anchor the head-tail coupling apparatus after meiosis. (3) Nematode paralogs that split the ancestral roles. UNC-84 (SF8) is the somatic anchor for UNC-83 (microtubule-motor nuclear migration) and ANC-1 (actin-based nuclear anchorage). SUN-1 (SF2) is the meiotic and embryonic partner of ZYG-12. (4) Drosophila Klaroid (SF8), the SUN partner of Klarsicht and Msp300 in nuclear migration, myonuclear positioning and germline centromere pairing. (5) The single fungal SUN proteins Sad1 (fission yeast) and Mps3 (budding yeast), both SF8. These anchor the spindle pole body to the nuclear envelope with KASH or KASH-like partners (Kms2, Mps2) and form meiotic telomere-bouquet LINC complexes (Sad1-Kms1; Mps3-Mps2-Csm4). (6) Plant Cter-SUN proteins (Arabidopsis SUN1 in SF8, SUN2 in SF47). They anchor plant-specific KASH proteins (WIP, SINE, TIK) and couple the nucleus to actin via WIT2-myosin XI-i. They also act in meiotic telomere attachment. The SUN-KASH anchoring activity and nuclear-envelope location are conserved across the family. The kind of cytoskeleton coupled (microtubules, actin, the spindle pole body) and the cell-cycle context (somatic, meiotic, spermiogenic) differ between lineages.

COQ4 is a zinc-binding protein of the mitochondrial CoQ synthome. It decarboxylates the 4-hydroxy-3-methoxy-5-polyprenylbenzoate intermediate of eukaryotic ubiquinone synthesis and organizes the COQ complex (S. cerevisiae COQ4, S. pombe coq4, human COQ4).

Gamma-glutamylcyclotransferase releases 5-oxoproline from gamma-glutamyl dipeptides in the gamma-glutamyl cycle (human GGCT). The family also contains fungal homologs in secondary-metabolite clusters such as Clonostachys VerK.

PIGT/Gpi16 proteins are components of the endoplasmic-reticulum GPI transamidase complex that attaches glycosylphosphatidylinositol anchors to proteins. Complex membership explains participation in the attachment reaction, while the catalytic chemistry belongs to the assembled machinery and its catalytic subunit. PIGT is not a generic soluble protease simply because the complex processes a protein precursor.

ALG10 (S. cerevisiae DIE2, S. pombe alg10, human ALG10/ALG10B) adds the terminal alpha-1,2-glucose to the lipid-linked oligosaccharide, completing Glc3Man9GlcNAc2-PP-Dol for oligosaccharyltransferase.

Zinc-dependent metalloenzymes of the PIG-L/MshB fold. Most characterized members are de-N-acetylases acting on N-acetylglucosamine-containing substrates: eukaryotic GlcNAc-PI de-N-acetylase (PIG-L, GPI-anchor biosynthesis; subfamily SF11, which also holds archaeal diacetylchitobiose deacetylase and mycobacterial mycothiol S-conjugate amidase) and actinobacterial MshB mycothiol-biosynthesis deacetylase (SF26). Subfamily SF29 holds Pseudomonas putida GalB, a zinc-containing 4-oxalomesaconate hydratase of gallate catabolism that does not hydrolyze an amide bond.

ALG1 adds the first, beta-1,4-linked mannose to GlcNAc2-PP-dolichol with GDP-mannose on the cytoplasmic face of the ER (S. cerevisiae ALG1, S. pombe alg1, human ALG1). Human ALG1L2 forms a separate, uncharacterized subfamily.

SPCS2/Spc2 proteins are membrane-associated accessory components of the eukaryotic signal peptidase complex. They promote complex activity and coordination with protein translocation, while SEC11-related subunits supply signal-peptide cleavage catalysis.

Animal phosphomevalonate kinase phosphorylates mevalonate 5-phosphate to mevalonate 5-diphosphate. It is a nucleoside-monophosphate-kinase-fold enzyme unrelated to the GHMP-type ERG8 of fungi.

Cystinosins are membrane proteins that export cystine from the lysosomal or vacuolar lumen. The experimentally annotated Drosophila Ctns record supports a cystine/proton transport function and a role in maintaining cysteine availability during fasting. Effects on mTORC1, autophagy and metabolism follow from this transport role and are not independent transport substrates.

PTHR13158 is the animal mitochondrial NAD(+) kinase family, distinct from the PTHR20275 family that holds cytosolic NADK and the fungal mitochondrial Pos5. Its characterised members are vertebrate NADK2: human NADK2 (Q4G0N4) phosphorylates NAD(+) with ATP or inorganic polyphosphate to make NADP(+), has only weak NADH kinase activity, is imported into mitochondria by an N-terminal transit peptide, and is the source of the mitochondrial NADP(H) pool; mouse Nadk2 is required for the same pool in vivo. Crystal structures show that NADK2 is a constitutively active dimer, held together by an insert (EMKA) found in the mitochondrial NAD kinases of animals that blocks the tetramer interface used by other NAD kinases. The PANTHER reference tree has 40 leaves. Its root (PTN004406956, also the SF5 node) is a horizontal-transfer node joining a eukaryotic clade (PTN000994636: bilaterians, a choanoflagellate, Plasmodium and Phytophthora) to one bacterial leaf, Leptospira interrogans LB_063. In the reference tree SF4 is a nematode-specific duplicate (C. elegans nadk-1) whose sister clade holds the nematode NADK2 orthologs (C. elegans nadk-2, SF5). C. elegans has no PTHR20275 member, so both of its members of the two NAD kinase families are in this family. About a third of the 3234 UniProtKB members are bacterial; only 1% of them match the Pfam NAD_kinase domain (72% of metazoan SF5 members do), most replace the second glycine of the GGDG block with Gln while keeping the catalytic Asp, and none has been characterised.

TRUB2-related proteins are associated with mitochondrial RNA pseudouridylation. Family membership supports an RNA-modification hypothesis but does not identify the RNA substrate or guarantee catalytic competence of a fragment.

Dolichol kinases phosphorylate the polyprenol carrier used in protein glycosylation and GPI-anchor synthesis, using CTP as donor. The integrated InterPro group also includes plant phytol kinases involved in tocopherol biosynthesis. The lipid substrate and metabolic pathway therefore need to be resolved independently of the shared membrane-associated kinase architecture.

KRIT1 and FRMD8 are FERM-domain interaction proteins with distinct partners. KRIT1 participates in the cerebral cavernous malformation signaling machinery and stabilizes endothelial junctions. FRMD8 binds iRhom proteins and protects the iRhom/ADAM17 sheddase complex from endolysosomal degradation, sustaining inflammatory and growth-factor ligand release.

Polytopic membrane-bound O-acyltransferase (MBOAT) proteins that move an acyl group from a donor on one side of a membrane to an acceptor on the other side or within the membrane. The family contains eukaryotic protein N-palmitoyltransferases that acylate the Hedgehog N-terminal cysteine (human HHAT, mouse Hhat, Drosophila Rasp), the HHAT paralog HHATL, the fungal GUP1/GUP2 proteins implicated in GPI-anchor lipid remodelling, and a large bacterial group in which the MBOAT protein partners with a DltD/SGNH-like extracytoplasmic protein to acylate cell-envelope polymers: DltB (D-alanylation of teichoic acids), PatA (peptidoglycan O-acetylation) and AlgI (alginate O-acetylation). Acyltransferase chemistry around the catalytic histidine conserved across MBOATs is shared, but donor, acceptor and the polymer or protein being modified differ between subfamilies, so only the broad acyltransferase function is family-wide.

The non-catalytic modifier subunit of glutamate-cysteine ligase lowers the Km of the catalytic subunit for glutamate and raises the Ki for glutathione feedback inhibition (human GCLM, S. pombe gcs2). S. cerevisiae has no member.

Family of Pex16/peroxin-16, one of the three "early" peroxins - with Pex3 and Pex19 - that build the peroxisomal membrane rather than filling it. Pex16 is an integral membrane protein with two transmembrane segments and both termini facing the cytosol. In mammals it is inserted cotranslationally into the ER, exported through Sec16B-dependent ER exit sites, and acts at the peroxisomal membrane as the anchoring receptor for Pex3, holding the Pex3-Pex19 carrier where newly synthesised peroxisomal membrane proteins can be delivered. Its loss is unusually severe among the peroxins: PEX16-deficient patient cells have no detectable peroxisomal membranes at all - not even the "ghosts" seen in matrix-import mutants - and re-expressing PEX16 rebuilds peroxisomes de novo, with membrane protein import preceding matrix protein import. Matrix import failure in PEX16-null cells is therefore a downstream consequence of having no organelle, not a function of Pex16. The family spans eukaryotes - the fetched slice runs from Yarrowia and S. pombe through Dictyostelium and Arabidopsis to fish, frog and mammals - and all reviewed members sit in a single subfamily. Taxonomic coverage in fungi is patchy, and at least one yeast lineage performs the equivalent ER-to-peroxisome PMP trafficking step with a non-orthologous protein (Pex36), so the family does not coincide with the function.

Plant cellulose synthases and related glycosyltransferases synthesize different glycan products. The retrieved group contains cellulose synthases, mixed-linkage glucan synthases and specialized small-molecule glycosyltransferases; the PANTHER X-box transcription-factor label is misleading for these members.

GNAT acetyltransferases that acetylate glucosamine 6-phosphate to GlcNAc 6-phosphate in UDP-GlcNAc synthesis (S. cerevisiae GNA1, S. pombe gna1, human GNPNAT1, plant GNA1). Smaller subfamilies hold bacterial and plastid GNATs of other specificity.

Members include bacterial rRNA methyltransferase RlmF, eukaryotic METTL16/U6 RNA methyltransferases and psilocybin synthase PsiM proteins. METTL16-dependent U6 modification connects RNA methylation to splicing; vertebrate MAT2A regulation is an additional regulatory deployment. Neither a U6 substrate nor RNA methylation itself follows automatically from this broad PANTHER assignment.

RPC4/C53 proteins are noncatalytic subunits of RNA polymerase III. They help organize the transcription complex and its initiation, termination and reinitiation behavior through association with other polymerase subunits. Participation in RNA synthesis does not mean that an isolated RPC4 protein catalyzes phosphodiester-bond formation.

Proteinaceous RNase P proteins use an RNA-recognition region and a nuclease domain to remove precursor tRNA 5-prime leaders. Plant PRORPs and animal mitochondrial RNase P catalytic subunits differ in compartment and partner dependence.

Tam41 (TAMM41 in animals) is the mitochondrial CDP-diacylglycerol (CDP-DAG) synthase. It converts phosphatidic acid and CTP to CDP-DAG on the matrix side of the mitochondrial inner membrane. This supplies the CDP-DAG used by Pgs1 and Crd1 for phosphatidylglycerol and cardiolipin synthesis. Tam41 is a nucleotidyltransferase-fold enzyme and is not related to the ER CDP-DAG synthase Cds1 (CDS1/CDS2), which belongs to a different family. Eukaryotic orthologs are single-copy, and the reviewed members (fungi, animals, Dictyostelium, plants) all sit in subfamily SF0.

Thiamine pyrophosphokinases transfer a pyrophosphate from ATP to thiamine, making the cofactor thiamine diphosphate (S. cerevisiae THI80, S. pombe tnr3, human TPK1, plant TPK1/2).

Eukaryotic family of small (~17-24 kDa) single-domain cytosolic and nuclear proteins built on a lipoyl-carrier-like barrel-sandwich hybrid fold (InterPro IPR039169 / Pfam PF01597 GCV_H / SUPERFAMILY SSF51230 Single hybrid motif) lacking a mitochondrial transit peptide or lipoyl-lysine motif. Across characterized bilaterians, ABITRAM (Simiate, formerly FAM206A) directly binds monomeric G-actin and filamentous F-actin to modulate actin filament polymerization and localizes to the cell nucleus. In jawed vertebrates, ABITRAM additionally localizes to SC35-positive nuclear speckles (resolved by STED nanoscopy in mouse brain slices to the speckle core domain)—where it associates with nuclear focal adhesion kinase (PTK2/FAK80) and is required for normal nuclear speckle organization and cell survival—and modulates cortical actin turnover in lamellipodia, filopodia tips, growth cones, and developing dendritic arbors, whereas in insects (Gerris buenoi) knockdown perturbs actin-bundled sensory bristles and embryonic leg elongation.

Fritz/WDPCP proteins organize cytoskeletal and membrane-associated machinery involved in cell polarity and ciliogenesis. Mammalian WDPCP participates in the CPLANE machinery that recruits intraflagellar transport components, while fly Fritz is associated with patterned wing-cell protrusions. These are related cellular organization functions, not evidence for a catalytic activity encoded by the WD-repeat fold.

The alpha-oxoamine synthase (AOS) family of pyridoxal 5'-phosphate (PLP)-dependent enzymes. Each condenses an amino acid with an acyl-CoA or acyl-ACP thioester, releasing CO2 (or, for KBL, cleaving the reverse way). The family includes several functionally distinct enzymes. 8-Amino-7-oxononanoate (KAPA) synthase, BioF, condenses L-alanine with pimeloyl-ACP or pimeloyl-CoA in biotin synthesis. Serine palmitoyltransferase (SPT) condenses L-serine with palmitoyl-CoA, the committed step of sphingolipid synthesis. Eukaryotic SPT is a heterodimer of the non-catalytic LCB1/SPTLC1 subunit and the PLP-binding LCB2/SPTLC2/SPTLC3 subunit; bacterial SPT is a homodimer. 5-Aminolevulinate synthase (ALAS) condenses glycine with succinyl-CoA, the first step of heme synthesis in animals, fungi and alpha-proteobacteria. 2-Amino-3-ketobutyrate CoA ligase (KBL/GCAT) works in threonine catabolism. Further members make bacterial signalling molecules (Vibrio CqsA, for the CAI-1 autoinducer) and fungal secondary metabolites (FUM8, ALT4, sphA).

ATP-dependent phosphofructokinases phosphorylate fructose 6-phosphate to fructose 1,6-bisphosphate, the committed and most regulated step of glycolysis. The family contains bacterial PfkA, the S. cerevisiae alpha/beta hetero-octamer (PFK1, PFK2), S. pombe pfk1 and the animal PFKM/PFKL/PFKP isozymes.

Family I CoA-transferases move coenzyme A from a donor acyl-CoA (usually succinyl-CoA or acetyl-CoA) to a carboxylic acid acceptor through a covalent glutamyl-CoA thioester intermediate. In bacteria the enzyme is a heteromer of separately encoded alpha (A) and beta (B) subunits: AtoD/AtoA acetoacetyl-CoA transferase of Escherichia coli, ScoA/ScoB succinyl-CoA:3-oxoacid CoA-transferases of Bacillus, Helicobacter and Mycobacterium, CtfA/CtfB of solventogenic Clostridium, and the PcaI/PcaJ 3-oxoadipate:succinyl-CoA transferase of the beta-ketoadipate pathway in Pseudomonas and Acinetobacter. In eukaryotes the two halves are fused into one polypeptide, the mitochondrial succinyl-CoA:3-ketoacid CoA-transferase (SCOT; human OXCT1 and the testis-specific OXCT2) that activates acetoacetate in extrahepatic ketone-body utilization. The family shares the CoA-transfer chemistry but differs in donor and acceptor specificity by clade. One clade, the IpdA subunits of the IpdAB enzyme of steroid-degrading Actinobacteria, belongs to an enzyme that has lost CoA transfer altogether and acts as a CoA-thioester ring-cleaving hydrolase; its partner IpdB is classified by PANTHER in a separate family (PTHR43293).

Integral-membrane CTP:phosphatidate cytidylyltransferases (CDP-diacylglycerol synthases, EC 2.7.7.41) that convert phosphatidic acid and CTP to CDP-diacylglycerol, the activated lipid donor for phosphatidylinositol and phosphatidylserine (and, in other compartments, phosphatidylglycerol/cardiolipin) synthesis. Members are eukaryotic ER-membrane enzymes (S. cerevisiae CDS1, S. pombe SPBC13A2.03, human CDS1/CDS2, fly Cds, worm cdgs-1, plant CDS1-3) plus Mycoplasma CdsA. The E. coli and B. subtilis CdsA proteins are in a separate PANTHER family (PTHR46382), and the mitochondrial CDP-DAG synthase Tam41 is an unrelated enzyme (PTHR13619).

PTHR13789 groups single-component FAD-dependent (group A flavoprotein) monooxygenases that use NAD(P)H and O2 to hydroxylate aromatic and heteroaromatic substrates. Characterized members include bacterial 6-hydroxynicotinate 3-monooxygenase NicC, urate hydroxylase HpxO, 3-hydroxybenzoate 6-hydroxylases, the phenazine hydroxylase PhzS, the flavonoid 8-hydroxylase FdeE (Hsero_1007) of naringenin degradation, and many fungal secondary-metabolite monooxygenases. Substrate and regiochemistry vary between subfamilies and even within them; the shared function is the flavin-dependent monooxygenase reaction class. NicC of aerobic nicotinate degradation performs an unusual decarboxylative hydroxylation of 6-hydroxynicotinate to 2,5-dihydroxypyridine, and its orthologues fall in two subfamilies (SF309 and SF318).

SARCOSINE DEHYDROGENASE-RELATED (PANTHER:PTHR13847) is characterized in PANTHER PAINT across 7 ancestral PTN node(s) (PANTHER:PTN000354057, PANTHER:PTN000354303, PANTHER:PTN001014589, PANTHER:PTN001014663 (+3 more)) with 11 IBD node assertion(s) and 0 term(s) carrying negated IRD/IKR branch blocks, covering cytoplasm (GO:0005737, CC), mitochondrion (GO:0005739, CC), mitochondrial matrix (GO:0005759, CC), late endosome (GO:0005770, CC) and 7 additional GO term(s). The family is a broad DAO-fold FAD oxidoreductase family; besides mitochondrial dimethylglycine and sarcosine dehydrogenases, FOXRED1, PDPR, D-amino acid dehydrogenases, glycine oxidase and MnmC, it contains the bacterial SoxB beta subunits of heterotetrameric sarcosine oxidase (in SF287).

Secreted prepro-peptide precursors of the vertebrate endothelin family (InterPro:IPR020475), comprising the three paralogous vertebrate isopeptide subfamilies Endothelin-1 (EDN1, PANTHER:PTHR13874:SF10), Endothelin-2 (EDN2, PANTHER:PTHR13874:SF9; which also contains the burrowing-asp venom sarafotoxins evolved in Atractaspis), and Endothelin-3 (EDN3, PANTHER:PTHR13874:SF11). Each preproendothelin is cleaved at dibasic sites by furin-like proprotein convertases to an inactive ~38-41-residue intermediate ("big endothelin") and subsequently cleaved at the Trp21-Val22/Ile22 bond by endothelin-converting enzymes (ECE1, ECE2) to yield the mature bioactive 21-residue bicyclic peptide stabilized by Cys1-Cys15 and Cys3-Cys11 disulfide bridges. Mature EDN1, EDN2, and EDN3 act as potent paracrine/autocrine peptide hormones (GO:0005179) that bind and activate the seven-transmembrane G protein-coupled receptors EDNRA (ETA, PANTHER:PTHR46099:SF2; selective for EDN1 and EDN2 over EDN3) and EDNRB (ETB, PANTHER:PTHR46099:SF3; equipotent for EDN1, EDN2, and EDN3), initiating the endothelin receptor signaling pathway (GO:0086100) and its canonical Gq/11-coupled phospholipase C-activating endothelin receptor signaling pathway (GO:0160135).

This heterogeneous family includes membrane-associated Bacillus BdbD, other DsbA-like oxidoreductases, thioredoxin-like reductases, GST-kappa-related proteins and SpxH adaptor proteins. BdbD directly oxidizes a protein-derived dithiol peptide, whereas PA14 DsbA2 is a distinct highly oxidizing protein in the Rv2466c-labelled subfamily. Neither the GST-kappa family label nor an individual DsbA-like representative defines the chemistry of the entire family.

Membrane-bound O-acyltransferases. Lysophospholipid acyltransferases (S. cerevisiae ALE1, S. pombe ale1, human LPCAT3, MBOAT1/2/7) reacylate lysophospholipids in the Lands cycle. The family also contains Porcupine, which palmitoleoylates Wnt proteins, and ghrelin O-acyltransferase (GOAT), which octanoylates ghrelin.

FAD-dependent (beta-alpha)8-barrel flavoenzymes that oxidize L-proline to 1-pyrroline-5-carboxylate and pass the electrons to the respiratory chain via ubiquinone. In eukaryotes they are mitochondrial inner-membrane enzymes that start proline catabolism (S. cerevisiae PUT1, the predicted fission yeast SPCC70.03c, human PRODH, Drosophila slgA, Arabidopsis POX1/POX2); bacterial monofunctional PRODHs such as Bacillus subtilis FadM and PutB and Thermus/Deinococcus enzymes belong to the same subfamily. Vertebrate PRODH2 (SF29) is a hydroxyproline dehydrogenase that strongly prefers trans-4-hydroxy-L-proline.

ESRP and hnRNP H/F-related proteins use RNA-recognition motifs in transcript processing and regulation. The retrieved family also includes GRSF1 and other RNA-binding proteins with distinct RNA targets and subcellular destinations.

Spt16 is the large subunit of FACT, a histone chaperone that reorganizes nucleosomes while preserving chromatin integrity. Its amino-terminal aminopeptidase-like fold binds histones H3 and H4. Structural and biochemical work on pombe Spt16 establishes a nonenzymatic histone-binding function for that fold, rather than aminopeptidase catalysis.

Dedicated J-domain co-chaperones of iron-sulfur cluster biogenesis. An N-terminal J-domain with the HPD motif stimulates ATP hydrolysis by the partner Hsp70 (bacterial HscA, mitochondrial HSPA9/mortalin, yeast Ssq1), and a C-terminal three-helix domain binds the cluster-loaded scaffold IscU/ISCU, so HscB delivers the scaffold to the chaperone and couples the ATPase cycle to cluster transfer. Members are proteobacterial HscB (Hsc20), yeast Jac1 and the mitochondrial HSCB/HSC20 of animals and plants; essentially all reviewed members fall in subfamily SF15.

PLP-dependent kynureninases hydrolyse 3-hydroxykynurenine (and kynurenine) to 3-hydroxyanthranilate (or anthranilate) and alanine on the kynurenine route of de novo NAD synthesis (S. cerevisiae BNA5, human KYNU, bacterial KynU). Some fungi have a second paralog (SF2).

A large family, mostly of integral-membrane CDP-alcohol phosphatidyltransferases (Pfam PF01066, CDP-OH_P_transf). These transfer the phosphatidyl group of CDP-diacylglycerol to different alcohol acceptors. The bacterial and plastid/plant PgsA-type PGP synthases use glycerol 3-phosphate. The eukaryotic mitochondrial cardiolipin synthases (CMP-forming) (yeast CRD1, S. pombe crd1, human CRLS1, plant CLS) use phosphatidylglycerol. The type-II phosphatidylserine synthases (yeast CHO1, S. pombe pps1, B. subtilis and mycobacterial PssA, P. putida PP_4677) use L-serine. PANTHER also places here proteins with only a haloacid-dehalogenase (HAD)-like hydrolase domain and no phosphatidyltransferase domain: human HDHD5/CECR5, yeast YKR070W and trypanosome and Candida CECR5-like proteins. These are related to the HAD domain that is fused N-terminal to the cardiolipin synthase domain in S. pombe crd1.

AFAP1, AFAP1L1 and AFAP1L2/XB130 are PH-domain-containing adaptor proteins associated with actin and membrane signaling. Their interaction regions recruit different signaling partners rather than catalyzing a shared chemical reaction. AFAP1L2 evidence for signal transduction should be interpreted in the context of that paralog's architecture and partners.

Bony-vertebrate (Euteleostomi) family of short-chain four-helix-bundle class I cytokines comprising two paralogous subfamilies: Interleukin-21 (PTHR14356:SF2, IL21) and Interleukin-15 (PTHR14356:SF3, IL15). Both cytokines signal through heteromeric class I cytokine receptor complexes that share the common cytokine receptor gamma chain (IL2RG/gamma-c) paired with a cytokine-specific receptor subunit (IL21R for IL21; IL2RB and trans-presenting IL15RA for IL15) to activate JAK1/JAK3 and downstream STAT transcription factors (predominantly STAT3/STAT1/STAT5 for IL21 and STAT5/STAT3 for IL15), coordinating NK cell, T cell, and B cell immunity.

The homo-oligomeric flavin-containing Cys decarboxylase (HFCD) family are FMN flavoproteins. They oxidize a cysteine thiol to a thioaldehyde so that the adjacent carboxylate can be decarboxylated, and their active sites lie at the subunit interfaces of a trimer (or larger oligomer). The main function is phosphopantothenoylcysteine decarboxylase (PPCDC/CoaC, EC 4.1.1.36), the third step of coenzyme A synthesis. It is carried by standalone eukaryotic enzymes (human PPCDC, Arabidopsis HAL3A/HAL3B) and by the N-terminal CoaC domain of bacterial and archaeal CoaBC. PANTHER subfamily SF6 also contains lantibiotic peptidyl-cysteine decarboxylases (S. epidermidis EpiD, Bacillus MrsD), which decarboxylate the C-terminal cysteine of a peptide rather than phosphopantothenoylcysteine. In hemiascomycete yeasts the PPCDC is an obligate heterotrimer. Cab3 (SF6) supplies the catalytic Cys, and Sis2/Hal3 or Vhs3 (SF17) supply the catalytic His; neither homotrimer is active. Sis2 and Vhs3 have a second, unrelated role as inhibitors of the Ppz1 protein phosphatase.

Rpa49 is an accessory subunit of RNA polymerase I that supports efficient ribosomal DNA transcription. The polymerase can retain activity when Rpa49 is deleted, indicating a stimulatory and organizational role rather than independent RNA polymerase catalysis. Its conserved function is linked to the specialized rRNA transcription machinery.

IPK1 phosphorylates the 2-position of inositol 1,3,4,5,6-pentakisphosphate to make phytic acid (IP6), the precursor of inositol pyrophosphates (S. cerevisiae IPK1, S. pombe ipk1, plant IPK1, human IPPK).

SHLD2 is a component of shieldin, a DNA-end protection complex acting in double-strand-break repair. Its DNA-associated and complex-assembly functions regulate access of repair machinery to damaged DNA. Shieldin participation is mechanistically distinct from DNA synthesis, helicase activity or nuclease activity.

Deuterostome family of giant spectrin-repeat proteins. It covers two chordate lineages that arose by a duplication (PANTHER node PTN000376568), plus a single-copy sea-urchin KASH protein. (1) The nesprin lineage has the vertebrate paralogs nesprin-1 (SYNE1, SF3) and nesprin-2 (SYNE2, SF4). These are the giant KASH proteins of the outer nuclear membrane. Their C-terminal KASH peptide binds SUN1/SUN2 trimers in the perinuclear space to form LINC complexes. Their N-terminal calponin-homology domains bind F-actin, and their spectrin-repeat rods recruit dynein-dynactin (via BICD2) and kinesin-1. In this way they anchor the cytoskeleton to the nuclear envelope and transmit the forces for nuclear migration, nuclear anchorage and centrosome-nucleus coupling. (2) The AKAP6 lineage (SF2, muscle A-kinase anchoring protein, mAKAP) is a PKA-anchoring signalling scaffold of the cardiac-myocyte nuclear envelope and sarcoplasmic reticulum. It organizes PKA, RyR2, PDE4D3 and PP2A. No vertebrate AKAP6 examined has a KASH domain, and it reaches the nuclear envelope indirectly by binding nesprin-1alpha. The single amphioxus member of the AKAP6 clade and the sea-urchin member (SF7) both keep a KASH domain. PANTHER's family name reflects the AKAP6 lineage only. The core molecular function of the family's best-studied members (nesprin-1/2) is nuclear-envelope cytoskeletal anchoring, not PKA anchoring. Invertebrate nesprin orthologs are classified in other PANTHER families (see notes).

SAM-dependent seven-beta-strand methyltransferases that methylate proteins: lysine methyltransferases of translation factors and chaperones (METTL21A, EEF1AKMT3, EEF2KMT, VCPKMT, yeast EFM2/EFM3/EFM7), histidine methyltransferases of ribosomal protein L3 (yeast HPM1, human METTL18) and the histone-arginine methyltransferase METTL23. In fission yeast the methyltransferase domain is fused to a C-terminal riboflavin-pathway pyrimidine deaminase domain (rib2, SF132).

Multi-pass endoplasmic-reticulum membrane enzymes of the steroid 5-alpha-reductase fold that carry out the middle step of the three-step route from polyprenol to dolichol: NADPH-dependent saturation of the alpha-isoprene unit of polyprenal to give dolichal. Characterized members are human SRD5A3 and budding-yeast Dfg10; the family also contains the fission-yeast ortholog (SPAC7D4.09c, dfg10), the Arabidopsis PPRD1 and PPRD2, and the fly, worm, mouse and rat orthologs. Loss of SRD5A3 causes SRD5A3-CDG; loss of Dfg10 lowers dolichol and causes hypoglycosylation in yeast.

WDR76/CMR1-related WD40 proteins have experimentally supported nuclear/chromatin associations in characterized homologs. Arabidopsis DRS1 has direct drought and ABA-dependent leaf-water-loss phenotypes, while its biochemical connection to chromatin remains unresolved. Broad DNA/chromatin association must be distinguished from a particular modified-base-reader mechanism.

Small (about 70-85 residues) two-pass endoplasmic-reticulum membrane proteins that form the regulatory subunit of the heterotrimeric dolichol-phosphate-mannose (Dol-P-Man) synthase, DPM1-DPM2-DPM3. DPM2 is non-catalytic: it stabilizes DPM3, which in turn tethers and stabilizes the soluble catalytic subunit DPM1, and it raises the activity of the enzyme. The family is present in animals, plants, Dictyostelium, Candida and fission yeast. It is absent from S. cerevisiae, whose Dol-P-Man synthase is a single membrane-anchored DPM1 polypeptide.

Cofactor-independent sugar epimerases and aldose-ketose isomerases built on the (alpha/alpha)6-barrel scaffold of N-acyl-D-glucosamine 2-epimerase (AGE). The reviewed members in the local inventory comprise vertebrate AGE (renin-binding protein, RENBP), bacterial cellobiose 2-epimerases, mannose 2-epimerases, D-mannose isomerases, a Rhizobium mannose-6-phosphate isomerase and the enterobacterial sulfoquinovose isomerase YihS. E. coli YihS, the first enzyme of the sulfoglycolytic Embden-Meyerhof-Parnas pathway, isomerizes beta-sulfoquinovose to 6-deoxy-6-sulfofructose and lacks AGE activity, although it retains weak isomerase activity on mannose, fructose, glucose, lyxose and xylulose.

Zinc-dependent amidohydrolases of the AspA/AstE fold that remove an N-acyl group from an L-amino acid. Three subfamilies carry different substrate specificities: animal aspartoacylase ASPA (SF9), which deacetylates N-acetyl-L-aspartate; animal ACY3 (SF5), an N-acyl-aromatic-L-amino acid amidohydrolase; and bacterial succinylglutamate desuccinylase AstE (SF7), which hydrolyzes N-succinyl-L-glutamate to glutamate and succinate as the last step of the arginine succinyltransferase (AST) pathway. SF7 also contains a cyanobacterial group named probable aspartoacylases. The shared chemistry is hydrolysis of a linear amide C-N bond; the acyl group and amino acid are set by subfamily.

The cached family records group catalytic nucleotide-binding subunits of rotary ATPases, including F-type ATP synthase beta and V-type ATPase A proteins. F-type complexes predominantly synthesize ATP using a proton gradient but retain regulated reverse ATP hydrolysis. Physiological reaction preference therefore cannot be used to reject hydrolysis capacity. Vacuolar localization and functional complex membership require separate phylogenetic and localization evidence. The family also contains the bacterial type III export ATPases (flagellar FliI and injectisome SctN), paralogs of F1-beta that assemble into FliH/FliI/FliJ-type cytoplasmic rings and hydrolyse ATP to release export chaperones and unfold substrates; they have no Fo sector and do not synthesize ATP.

Animal-restricted family (3,456 InterPro-classified proteins across 1,095 proteomes) of small tail-anchored outer mitochondrial membrane proteins built from three conserved elements: an N-terminal LC3-interacting region (LIR, core S-W-[VI]-E-L), a weak BH3-like segment, and a C-terminal transmembrane helix that both anchors the protein in the outer mitochondrial membrane and drives homodimerization. The vertebrate paralogs BNIP3 (subfamily SF4) and BNIP3L/NIX (SF3) are the best-studied receptor- mediated mitophagy proteins in metazoa: their LIR binds Atg8-family proteins (LC3/GABARAP) to tether mitochondria to forming autophagosomes, NIX is required for programmed mitochondrial clearance during reticulocyte maturation, and BNIP3 is a HIF-1 target that drives hypoxia-induced mitophagy and, from its ER-resident pool, reticulophagy. The single invertebrate orthologs (subfamily SF5; C. elegans DCT-1, Drosophila BNIP3) retain the same LIR, BH3-like and TM architecture, and DCT-1 is the principal stress-induced mitophagy receptor of C. elegans. Overexpression of every well-studied member kills cultured cells, but the death is BH3- and caspase- independent for DCT-1 and largely context-dependent (hypoxia, necrosis-like) for the vertebrate proteins; the conserved, physiologically demonstrated activity of the family is mitophagy-receptor function.

Symplekin and Pta1 are scaffolding components of eukaryotic RNA 3-prime-end processing machinery. They organize cleavage/polyadenylation factors and associated regulatory components. Historical names referring to pre-tRNA processing do not define an intrinsic endonuclease reaction for the family.

DGCR2-related proteins are membrane-associated interaction proteins with extracellular-domain architecture. Mouse DGCR2 participates in cortical-neuron migration and associates with the Reelin signaling complex; the conserved ligand and signaling role of divergent fly CG42404 remain unresolved.

A eukaryotic family of multi-pass ER-membrane enzymes that work on phospholipid head groups. It contains two functionally distinct groups. The first is the CDP-diacylglycerol--inositol 3-phosphatidyltransferases (PI synthases): yeast PIS1, S. pombe pis1, human CDIPT, Drosophila Pis and Arabidopsis PIS1/PIS2. These transfer the phosphatidyl group of CDP-DAG to myo-inositol, which is the only de novo route to phosphatidylinositol. The second is the animal and plant base-exchange phosphatidylserine synthases (PTDSS1, PTDSS2, plant PSS). These swap the head group of phosphatidylcholine or phosphatidylethanolamine for L-serine and do not use CDP-DAG. S. cerevisiae and S. pombe have only the PI synthase branch. Their CDP-DAG-dependent PS synthase (CHO1, pps1) is in the unrelated family PTHR14269.

Family of endoplasmic-reticulum-lumenal lectins built around the mannose 6-phosphate receptor homology (MRH) domain: fungal Yos9, plant OS9, and the two vertebrate paralogs OS-9 and ERLEC1 (XTP3-B/Erlectin). Members are soluble, signal-peptide-bearing ER lumen residents that act as glycan-reading substrate receptors in ER-associated degradation (ERAD): the MRH pocket recognizes trimmed high-mannose N-glycans exposing a terminal alpha-1,6-linked mannose on misfolded glycoproteins, and the lectin hands the substrate, via the SEL1L (yeast Hrd3) adaptor, to the HRD1 ubiquitin ligase complex for retrotranslocation and proteasomal degradation. This role is conserved from fungi through plants to vertebrates - the fetched 24-member slice spans yeasts (S. cerevisiae Yos9, S. pombe yos9), filamentous fungi, Arabidopsis and rice OS9, Xenopus and mammals - and the family's PAINT node is accordingly placed at the eukaryote root. Within mammals the two paralogs partition the work with regulatory nuance: OS-9 and ERLEC1 redundantly promote glycoprotein ERAD and stabilize the SEL1L-HRD1 complex, while ERLEC1 additionally restrains degradation of non-glycosylated substrates, an activity OS-9 antagonizes. Domain composition varies (human OS-9 has one MRH domain, ERLEC1 has two, of which only the C-terminal MRH2 is a functional glycan-binding module), but the core function - ER-lumenal misfolded-glycoprotein recognition for ERAD - is uniform.

Erg28 is a small ER membrane protein with no catalytic activity. It tethers the C-4 sterol demethylation enzymes (Erg25, Erg26, Erg27) and Erg6 into a complex for efficient ergosterol synthesis (S. cerevisiae ERG28, S. pombe erg28; animal C14orf1/ERG28 homologs).

Small, multi-pass ER-membrane phospholipid N-methyltransferases that use S-adenosyl-L-methionine to methylate the ethanolamine head group of phosphatidylethanolamine (PE) and its partly methylated derivatives, producing phosphatidylcholine (PC). In fungi the member OPI3/PEM2 (S. pombe cho1, Neurospora chol-2, Aspergillus choC) mainly makes the second and third methylations, PMME to PDME to PC, after the unrelated CHO2 (PTHR32138) has made the first. Animal PEMT makes all three methylations by itself. Plant PLMT methylates the partly methylated intermediates. The family is unrelated to the fungal CHO2 family.

Non-heme Fe(II) cupin dioxygenases that open the ring of 3-hydroxyanthranilate, giving the precursor of quinolinate in de novo NAD synthesis (S. cerevisiae BNA1, human HAAO, bacterial NbaC).

Mastermind proteins are transcriptional coactivators of the Notch pathway. The conserved N-terminal MamL-1 domain (Pfam PF09596) forms an extended helix. That helix binds the groove created when the Notch intracellular domain (NICD) ankyrin repeats dock onto the CSL DNA-binding protein, completing the NICD-CSL-MAML ternary activation complex. The long, disordered C-terminal regions recruit histone-acetyltransferase and Mediator-associated activities. Vertebrates have three paralogues, MAML1, MAML2 and MAML3. MAML1 was cloned as the human homologue of Drosophila mastermind and shown to bind all four NOTCH ankyrin domains and amplify NOTCH-induced transcription. The family also holds invertebrate and cnidarian MamL-1-domain proteins (SF20). However, PANTHER classifies Drosophila melanogaster Mastermind, and the other cyclorrhaphan fly Mastermind proteins, outside this family. It places them in PTHR16431, the Mis18 family. The C. elegans Mastermind-role protein SEL-8/LAG-3 has no MamL-1 domain and no PANTHER family.

Pcf11 couples RNA polymerase II termination to pre-mRNA 3-prime-end processing through interactions with the polymerase and cleavage/polyadenylation machinery. Its function depends on a multidomain protein and association with factors such as Clp1. A short fragment matching part of Pcf11 cannot be assumed to carry all functions of the intact protein.