id: MODULE:nad_consumption title: NAD+ consumption — sirtuin deacylation, PARP/ARTD poly- and mono-ADP-ribosylation and CD38/BST1 NAD+ glycohydrolysis, with PARG and macrodomain reversal; SIRT1-7/PARP1-4/PARP6/PARP8-12/PARP14-16/TIPARP/TNKS/TNKS2/CD38/BST1/PARG/MACROD1/MACROD2/OARD1 description: >- Besides serving as a hydride carrier in redox reactions, NAD+ is a substrate that is broken down by three classes of signalling enzymes. Each cleaves the bond between nicotinamide and ribose, releases free nicotinamide and uses the ADP-ribose moiety. The sirtuins (SIRT1-7) are NAD+-dependent protein deacylases. They transfer an acetyl group, or another acyl group such as succinyl, malonyl, glutaryl, lipoyl or a long-chain fatty acyl, from a protein lysine to the ADP-ribose of NAD+, producing nicotinamide and 2''-O-acyl-ADP-ribose. SIRT1, SIRT6 and SIRT7 act in the nucleus, SIRT2 mainly in the cytoplasm, and SIRT3, SIRT4 and SIRT5 in mitochondria. SIRT5 is chiefly a desuccinylase, demalonylase and deglutarylase, SIRT4 a lipoamidase, and SIRT4 and SIRT6 also mono-ADP-ribosylate proteins. The PARP (ARTD) family of ADP-ribosyltransferases transfers ADP-ribose from NAD+ to protein acceptor residues. PARP1, PARP2 and the tankyrases TNKS and TNKS2 build poly(ADP-ribose) chains; DNA-break-activated PARP1, with its cofactor HPF1, is the largest NAD+ consumer after genotoxic stress. Most other PARPs (PARP3, PARP4, PARP6, PARP8, PARP10-12, PARP14-16 and TIPARP/PARP7) attach a single ADP-ribose. The ectoenzymes CD38 and BST1 (CD157) are NAD+ glycohydrolases and ADP-ribosyl cyclases. They convert NAD+ mostly to ADP-ribose and partly to the calcium-mobilising messenger cyclic ADP-ribose, which they also hydrolyse. Protein ADP-ribosylation is reversed by PAR glycohydrolase (PARG), which cleaves PAR chains, and by the macrodomain hydrolases MACROD1, MACROD2 and OARD1 (TARG1), which remove the last ADP-ribose from glutamate and aspartate residues. The nicotinamide released by all of these reactions is recycled to NAD+ by the NAMPT salvage pathway. Because the consumers share a limited NAD+ pool, strong PARP1 or CD38 activity lowers NAD+ and with it sirtuin activity, coupling DNA damage, inflammation and ageing to metabolic signalling. status: DRAFT scope: CONCRETE evidence: - source_id: PW:0002581 title: nicotinamide adenine nucleotide utilization pathway statement: >- The module boundary and gene set follow the RGD Pathway Ontology record and diagram for this term. The diagram draws the NAD+ biosynthetic pathway (PW:0000219) positively affecting NAD+, and NAD+ positively affecting target deacetylation (sirtuins), target ribosylation (MAR/PAR writers, the PARPs) and cyclic ADP-ribose (Cd38, Bst1); target ribosylation positively affects target deribosylation (MAR/PAR erasers), and MAR/PAR readers are associated with target ribosylation. The RGD human gene set is APLF, BST1, CD38, CHFR, MACROD1, MACROD2, OARD1, PARG, PARP1-4, PARP6, PARP8-12, PARP14-16, RNF146, SIRT1-7, TIPARP, TNKS, TNKS2 and ZC3HAV1. Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0002581.yaml). - source_id: PW:0002582 title: ADP-ribosylation pathway, mono and poly-ribosylation statement: >- The mono- and poly-ADP-ribosylation subpathway drawn as a node of the PW:0002581 diagram; covered by the ADP-ribosyltransferase variant and the eraser part of this module. - source_id: PW:0002583 title: ADP-ribosylation pathway, cyclic ribosylation statement: >- The cyclic ADP-ribosylation subpathway drawn as a node of the PW:0002581 diagram; covered by the CD38/BST1 variant. - source_id: PW:0002584 title: sirtuin mediated pathway statement: >- The sirtuin-mediated subpathway drawn as a node of the PW:0002581 diagram; covered by the sirtuin variant. - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0002581.yaml title: RGD PW:0002581 record text (project snapshot) statement: >- The RGD record states that NAD+ is a substrate, not only a redox cofactor, for the three consumer classes and that they compete for it. supporting_text: Competition between NAD-consuming enzymes for the limited shared substrate is envisioned. - source_id: GO:0019677 title: NAD+ catabolic process statement: >- The curated closeMatch GO mapping for PW:0002581 (projects/RGD_PATHWAY_ONTOLOGY/data/pw_go_curated.sssom.yaml). - source_id: PMID:25043379 title: Family-wide analysis of poly(ADP-ribose) polymerase activity. statement: >- The family-wide PARP activity study that assigns poly- versus mono-ADP-ribosylation to each PARP, used for the ART variant split. supporting_text: Here we show that the majority of PARPs generate MAR, not PAR, and demonstrate that the H-Y-E motif is not the sole indicator of PARP activity. notes: >- Derived from the RGD Pathway Ontology record and diagram PW:0002581 (nicotinamide adenine nucleotide utilization pathway) through the RGD_PATHWAY_ONTOLOGY project's diagram->module route; curated GO mapping GO:0019677 NAD+ catabolic process (skos:closeMatch). The RGD diagram supplies the boundary (NAD+ in; target deacetylation, target ribosylation, cyclic ADP-ribose and target deribosylation out) and the 33-gene human set. It is modelled as two required parts and one optional part: (1) a variant set of the three NAD+-consuming enzyme classes, sirtuins, PARP/ARTD ADP-ribosyltransferases (split into poly- and mono-ADP-ribosylation) and the CD38/BST1 NAD+ glycohydrolases/ADP-ribosyl cyclases; (2) the hydrolytic reversal of protein ADP-ribosylation by PARG and the macrodomain hydrolases; and (3) an optional module_ref to the NAMPT/NMN realization of modules/nad_biosynthesis_salvage.yaml, which recycles the released nicotinamide. The three RGD subpathway terms drawn as diagram nodes (PW:0002582, PW:0002583, PW:0002584) are listed as evidence because the variants cover them. The fourth diagram link, PW:0000219 NAD+ biosynthetic pathway, is not: NAD+ synthesis is modelled in modules/nad_biosynthesis_salvage.yaml and modules/kynurenine_nad_de_novo.yaml and is only referenced here. Boundary decisions. (a) PAR readers APLF, CHFR and RNF146 are context, not participants. Each binds poly(ADP-ribose) (GO:0072572, IDA; PMID:18172500, PMID:21478859), but none consumes NAD+ or transfers or removes ADP-ribose. Their own activities (APLF histone chaperone and nuclease, CHFR and RNF146 ubiquitin ligase) act downstream in DNA repair, mitotic checkpoint control and tankyrase-directed proteolysis of AXIN. RGD itself draws the readers only as associated with target ribosylation. (b) ZC3HAV1 (PARP13, ZAP) is excluded. Its reviewed UniProt entry Q7Z2W4 states that its divergent PARP-homology domain lacks the structural requirements for NAD+ binding and is inactive. QuickGO (checked 2026-10-28) records NOT NAD+-protein mono-ADP-ribosyltransferase activity (IDA, PMID:25043379), NOT NAD+ poly-ADP-ribosyltransferase activity and NOT NAD+ binding (IMP, PMID:25635049). Its antiviral RNA-binding role is unrelated to NAD+ consumption. (c) PARP9 is in neither the RGD gene list nor the participant set, and its catalytic status is disputed. QuickGO carries both NOT GO:0003950 and NOT NAD+ binding (IMP, PMID:16061477) and positive GO:0140802 C-terminal glycine ADP-ribosyltransferase (IDA, PMID:28525742, ubiquitin ADP-ribosylation by the DTX3L-PARP9 heterodimer) and GO:0003950 (IDA, PMID:23230272). PMID:27796300 found that PARP9 does not ADP-ribosylate STAT1 and instead suppresses PARP14. This is recorded as a knowledge gap. (d) GO usage of GO:0019677. In human GOA the term is carried only by NAD+-degrading enzymes: SARM1 (IDA, many papers), NUDT12 (IDA), NUDT17 (IBA), plus IEA rows on NNMT and PARP14 (GO_REF:0000107). No sirtuin or PARP carries it, because GO describes their process as protein deacylation or ADP-ribosylation, with NAD+ as cosubstrate. GO:0019677 is therefore kept as the module-level concept (the closeMatch) and is not put on the sirtuin or PARP annotons. It is put on the CD38 and BST1 annotons, because their NAD+ glycohydrolase chemistry (NAD+ to ADP-ribose or cADPR plus nicotinamide) is the same as that of SARM1, whose GO:0019677 annotation rests on IDA. Neither CD38 nor BST1 carries GO:0019677 in GOA; this is a possible curation gap, not asserted here as a GOA annotation. The PARP14 IEA row looks like an over-propagated orthology transfer and is a candidate for upstream review. (e) Molecular functions come from each protein's experimental GO annotations in QuickGO (checked 2026-10-28), cross-checked against the Rhea xrefs of the GO terms and the cached abstracts: SIRT1, SIRT2, SIRT3, SIRT6 and SIRT7 GO:0034979 (EXP/IDA; RHEA:43636); SIRT5 GO:0036055 (IDA; RHEA:47668; demalonylase GO:0036054 and deglutarylase GO:0061697 in prose); SIRT4 GO:0106419 (EXP/IDA; RHEA:63640) and GO:0140803 (EXP; RHEA:56612); SIRT6 GO:0140804 (EXP; RHEA:58220); PARP1 GO:0140805 (EXP/IDA; RHEA:58232) and GO:0003950 (EXP/IDA); PARP2, TNKS and TNKS2 GO:0003950 (IDA/EXP); PARP3, PARP4, PARP8, PARP11, PARP12, PARP15 and TIPARP GO:1990404 (IDA); PARP6 GO:0140803 (IDA); PARP10, PARP14 and PARP16 GO:0140807 (EXP/IDA; RHEA:58224); CD38 and BST1 GO:0061809 (EXP/IDA; RHEA:38611, RHEA:38615, plus NAD+ hydrolysis RHEA:16301); PARG GO:0004649 (EXP/IDA; RHEA:52216); MACROD1, MACROD2 and OARD1 GO:0140293 (IDA; RHEA:58248). PAR chain elongation (EC 2.4.2.30) has no Rhea reaction, so the PAR annotons carry the EC equation in prose. Most PARP mono-ARTs (PARP3, PARP4, PARP6, PARP8, PARP10, PARP11, PARP12, PARP14, PARP15, PARP16, TIPARP) also carry GO:0003950 poly-ADP-ribosyltransferase activity in GOA, by IBA and in some cases IDA/IMP. That conflicts with the family-wide product assignment (PMID:25043379), which found that most PARPs make MAR, and with the substrate-assisted mechanism that prevents PARP10-type enzymes from polymerising (PMID:18851833). These rows are candidates for IBA and upstream review, and GO:0003950 is not used for them here. Also not adopted: SIRT7 protein methyltransferase activity (GO:0008276, IDA; also an activity in GO-CAM gomodel:63c0ac2b00001853). It is unexpected for a sirtuin and is flagged for review. (f) Outside the RGD gene list and the module: the serine-ADP-ribose hydrolase ADPRS (ARH3), which removes the HPF1-dependent serine mono-ADP-ribose that PARG leaves; the NUDIX ADP-ribose pyrophosphatases (NUDT5, NUDT9) that clear free ADP-ribose; the NAD+ hydrolase SARM1; the ecto-ARTs ART1-5; and NNMT, which methylates the nicotinamide product. The ADPRS omission means the reversal part as drawn by RGD is incomplete for serine-linked marks. The PARP1 cofactor HPF1 is described in the PARP1 annoton but is not a participant. Downstream signalling by cADPR (ryanodine receptors) and NAADP (two-pore channels) is out of scope. (g) GO-CAM: gocams/index.tsv (checked 2026-10-28) has production models for 12 of the 33 genes. The project's best-overlap model gomodel:627d95ee00002067 is linked at module level and on the PARP1 and PARP2 annotons, and further models are linked on the SIRT1, SIRT2, SIRT3, SIRT6, SIRT7, PARP1, PARP2, PARP12 and PARP16 annotons. Possible GO-CAM issue: in gomodel:696022cd00000603 (Regulation of the TCA cycle by SIRT3) the SIRT3 deacetylase activity is part of GO:0008053 mitochondrial fusion, which does not match the model title. Gene reviews exist for PARP1, SIRT1, SIRT2, SIRT5 and TNKS; the other members have none. Publications cited are abstract-only in the cache except PMID:22076378, PMID:25525879, PMID:27568560, PMID:28190768, PMID:23481255, PMID:23275542, PMID:27796300, PMID:30104678 and PMID:34314702. knowledge_gaps: - gap_statement: >- Whether PARP9 has ADP-ribosyltransferase activity of its own, and whether the ubiquitin Gly76 ADP-ribosylation attributed to the DTX3L-PARP9 heterodimer is catalysed by PARP9 or by DTX3L, is unresolved. boundary: >- PARP9 lacks the canonical NAD+-binding features and is excluded from the participant set. One study reports NAD+-dependent ubiquitin ADP-ribosylation by the heterodimer, while another found that PARP9 does not ADP-ribosylate STAT1 and that it suppresses PARP14 activity. gap_kind: - BIOLOGY status: OPEN significance: >- Decides whether PARP9 is an NAD+ consumer and belongs among the mono-ADP-ribosyltransferases of this module or is a non-catalytic PAR reader. resolution: >- Assay recombinant DTX3L-PARP9 heterodimers carrying catalytic-site substitutions in each partner separately for NAD+ consumption and ubiquitin ADP-ribosylation, and measure ADP-ribosylated ubiquitin in PARP9-null cells reconstituted with wild-type or catalytic-site mutant PARP9. provenance: - reference_id: PMID:28525742 supporting_text: We show that the Dtx3L/Parp9 heterodimer mediates NAD+-dependent mono-ADP-ribosylation of ubiquitin - reference_id: PMID:27796300 supporting_text: PARP9 did not promote ADP-ribosylation of either STAT1α or STAT6, which supports a previous report showing that PARP9 lacks catalytic activity - gap_statement: >- The share of cellular NAD+ turnover carried by each consumer class (sirtuins, PARPs, CD38/BST1) in human tissues at rest, and how it shifts with DNA damage, inflammation and age, is not quantified. boundary: >- Maximal PARP1 activation can deplete NAD+ by most of its pool, and CD38 hydrolyses about 100 NAD+ per cADPR made, but direct flux measurements that apportion NAD+ consumption between the classes in the same tissue are lacking. gap_kind: - BIOLOGY status: OPEN significance: >- Determines which consumer drives the NAD+ decline linked to ageing and DNA damage, and so which branch of this module limits sirtuin activity. resolution: >- Isotope-tracer NAD+ flux measurement in human cells and tissues with selective PARP1/2, CD38 and sirtuin inhibition or knockout, under basal, genotoxic and inflammatory conditions. provenance: - reference_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0002581.yaml supporting_text: Competition between NAD-consuming enzymes for the limited shared substrate is envisioned. module: id: nad_consumption label: NAD+ consumption by sirtuins, ADP-ribosyltransferases and NAD+ glycohydrolases module_type: METABOLIC_PATHWAY description: >- Sirtuins, PARP-family ADP-ribosyltransferases and the CD38/BST1 NAD+ glycohydrolases each cleave NAD+ and release nicotinamide; the protein ADP-ribosylation made by PARPs is reversed by PARG and the macrodomain hydrolases, and the nicotinamide is salvaged to NAD+ by NAMPT. concepts: - preferred_term: NAD+ catabolic process term: id: GO:0019677 label: NAD+ catabolic process description: >- closeMatch mapping of PW:0002581; the module covers NAD+ breakdown by enzymes that use it as a substrate. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens description: >- Members are grounded on the human proteins; the RGD diagram is drawn for rat and the gene set is conserved in mammals. parts: - order: 1 role: NAD+ cleavage with nicotinamide release by a consumer enzyme node: id: nad_consuming_reactions label: NAD+-consuming enzyme classes module_type: METABOLIC_PATHWAY description: >- Three enzyme classes use NAD+ as a substrate rather than as a redox cofactor. Each cleaves the nicotinamide-ribosyl bond, releases nicotinamide and destroys the NAD+ molecule. concepts: - preferred_term: NAD+ catabolic process term: id: GO:0019677 label: NAD+ catabolic process description: >- The breakdown of NAD+ that these consumers effect jointly; see notes for how GO applies the term. variant_sets: - id: nad_consumer_class label: NAD+-consuming enzyme class axis: enzyme class (sirtuin deacylase, ADP-ribosyltransferase, NAD+ glycohydrolase/cyclase) selection: ONE_OR_MORE variants: - id: sirtuin_nad_consumption label: Sirtuin NAD+-dependent deacylation and ADP-ribosylation module_type: MOLECULAR_FUNCTION description: >- Class III protein deacylases (sirtuins 1-7) share a conserved NAD+-binding catalytic core. They cleave the nicotinamide-ribosyl bond of NAD+ and transfer the protein acyl group to the ADP-ribose, so every deacylation consumes one NAD+ and yields nicotinamide and 2''-O-acyl-ADP-ribose. Nicotinamide is a non-competitive feedback inhibitor, which makes sirtuin activity sensitive to the NAD+/nicotinamide ratio. variant_sets: - id: sirtuin_reaction label: Sirtuin reaction axis: acyl group removed or ADP-ribose transferred selection: ONE_OR_MORE variants: - id: sirtuin_deacetylation label: NAD+-dependent lysine deacetylation (SIRT1, SIRT2, SIRT3, SIRT6, SIRT7) module_type: REACTION description: >- Removal of an acetyl group from a protein lysine with NAD+ as cosubstrate. The ADP-ribose of NAD+ accepts the acetyl group, so each deacetylation consumes one NAD+ and releases nicotinamide and 2''-O-acetyl-ADP-ribose. annotons: - id: sirt1_deacetylase label: SIRT1 NAD-dependent protein lysine deacetylase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SIRT1 term: id: UniProtKB:Q96EB6 label: NAD-dependent protein deacetylase sirtuin-1 function: preferred_term: NAD-dependent protein lysine deacetylase activity term: id: GO:0034979 label: NAD-dependent protein lysine deacetylase activity substrates: - preferred_term: N6-acetyl-L-lysyl-[protein] term: id: CHEBI:61930 label: N(6)-acetyl-L-lysine residue - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) - preferred_term: water term: id: CHEBI:15377 label: water products: - preferred_term: L-lysyl-[protein] term: id: CHEBI:29969 label: L-lysinium residue - preferred_term: 2''-O-acetyl-ADP-D-ribose term: id: CHEBI:83767 label: 2''-O-acetyl-ADP-D-ribose(2-) - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide evidence: - source_id: RHEA:43636 statement: >- N(6)-acetyl-L-lysyl-[protein] + NAD(+) + H2O = 2''-O-acetyl-ADP-D-ribose + nicotinamide + L-lysyl-[protein]; the Rhea xref of GO:0034979 (EC 2.3.1.286). processes: - preferred_term: protein deacetylation term: id: GO:0006476 label: protein deacetylation locations: - preferred_term: nucleus term: id: GO:0005634 label: nucleus role_description: >- Nuclear sirtuin and the best-characterised NAD+-dependent deacetylase; deacetylates histones and many transcription factors and coregulators, including p53 at Lys382. gocam_associations: - model: gomodel:61f34dd300000981 activity: gomodel:61f34dd300000981/61f34dd300001021 title: Regulation of gluconeogenesis by SIRT6, FOXO1 and KAT2A/GCN5 (Human) description: >- SIRT1 GO:0034979 NAD-dependent protein lysine deacetylase activity in the nucleus. evidence: - source_id: PMID:11672523 statement: >- Human SIRT1 is an NAD-dependent deacetylase of p53. supporting_text: binds and deacetylates the p53 protein with a specificity for its C-terminal Lys382 residue - id: sirt2_deacetylase label: SIRT2 NAD-dependent protein lysine deacetylase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SIRT2 term: id: UniProtKB:Q8IXJ6 label: NAD-dependent protein deacetylase sirtuin-2 function: preferred_term: NAD-dependent protein lysine deacetylase activity term: id: GO:0034979 label: NAD-dependent protein lysine deacetylase activity substrates: - preferred_term: N6-acetyl-L-lysyl-[protein] term: id: CHEBI:61930 label: N(6)-acetyl-L-lysine residue - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) - preferred_term: water term: id: CHEBI:15377 label: water products: - preferred_term: L-lysyl-[protein] term: id: CHEBI:29969 label: L-lysinium residue - preferred_term: 2''-O-acetyl-ADP-D-ribose term: id: CHEBI:83767 label: 2''-O-acetyl-ADP-D-ribose(2-) - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide evidence: - source_id: RHEA:43636 statement: >- N(6)-acetyl-L-lysyl-[protein] + NAD(+) + H2O = 2''-O-acetyl-ADP-D-ribose + nicotinamide + L-lysyl-[protein]; the Rhea xref of GO:0034979 (EC 2.3.1.286). processes: - preferred_term: protein deacetylation term: id: GO:0006476 label: protein deacetylation locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Predominantly cytoplasmic sirtuin that deacetylates alpha-tubulin and, at the G2/M transition, histone H4K16; it also removes long-chain fatty acyl groups (demyristoylase/depalmitoylase activity, retained in the SIRT2 gene review). gocam_associations: - model: gomodel:62900b6400000500 activity: gomodel:62900b6400000500/62900b6400000560 title: Regulation of ACLY by acetylation by PCAF/KAT2B and ubiquitination (by UBR4) (Human) description: >- SIRT2 GO:0034979 NAD-dependent protein lysine deacetylase activity on ACLY. evidence: - source_id: PMID:16648462 statement: >- SIRT2 deacetylates histone H4K16Ac in vitro and in vivo. supporting_text: SirT2 and its yeast counterpart Hst2 have a strong preference for histone H4K16Ac in their deacetylation activity in vitro and in vivo - id: sirt3_deacetylase label: SIRT3 NAD-dependent protein lysine deacetylase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SIRT3 term: id: UniProtKB:Q9NTG7 label: NAD-dependent protein deacetylase sirtuin-3, mitochondrial function: preferred_term: NAD-dependent protein lysine deacetylase activity term: id: GO:0034979 label: NAD-dependent protein lysine deacetylase activity substrates: - preferred_term: N6-acetyl-L-lysyl-[protein] term: id: CHEBI:61930 label: N(6)-acetyl-L-lysine residue - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) - preferred_term: water term: id: CHEBI:15377 label: water products: - preferred_term: L-lysyl-[protein] term: id: CHEBI:29969 label: L-lysinium residue - preferred_term: 2''-O-acetyl-ADP-D-ribose term: id: CHEBI:83767 label: 2''-O-acetyl-ADP-D-ribose(2-) - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide evidence: - source_id: RHEA:43636 statement: >- N(6)-acetyl-L-lysyl-[protein] + NAD(+) + H2O = 2''-O-acetyl-ADP-D-ribose + nicotinamide + L-lysyl-[protein]; the Rhea xref of GO:0034979 (EC 2.3.1.286). processes: - preferred_term: protein deacetylation term: id: GO:0006476 label: protein deacetylation locations: - preferred_term: mitochondrial matrix term: id: GO:0005759 label: mitochondrial matrix role_description: >- Major deacetylase of the mitochondrial matrix; activates glutamate dehydrogenase, isocitrate dehydrogenase 2 and other metabolic enzymes by deacetylation. gocam_associations: - model: gomodel:696022cd00000603 activity: gomodel:696022cd00000603/696022cd00000604 title: Regulation of the TCA cycle by SIRT3 (Human) description: >- SIRT3 GO:0034979 NAD-dependent protein lysine deacetylase activity in the mitochondrial matrix. evidence: - source_id: PMID:18680753 statement: >- SIRT3 deacetylates and activates mitochondrial matrix glutamate dehydrogenase. supporting_text: We show that Sirt3 can deacetylate and thereby activate a central metabolic regulator in the mitochondrial matrix, glutamate dehydrogenase - id: sirt6_deacetylase label: SIRT6 NAD-dependent protein lysine deacetylase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SIRT6 term: id: UniProtKB:Q8N6T7 label: NAD-dependent protein deacylase sirtuin-6 function: preferred_term: NAD-dependent protein lysine deacetylase activity term: id: GO:0034979 label: NAD-dependent protein lysine deacetylase activity substrates: - preferred_term: N6-acetyl-L-lysyl-[protein] term: id: CHEBI:61930 label: N(6)-acetyl-L-lysine residue - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) - preferred_term: water term: id: CHEBI:15377 label: water products: - preferred_term: L-lysyl-[protein] term: id: CHEBI:29969 label: L-lysinium residue - preferred_term: 2''-O-acetyl-ADP-D-ribose term: id: CHEBI:83767 label: 2''-O-acetyl-ADP-D-ribose(2-) - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide evidence: - source_id: RHEA:43636 statement: >- N(6)-acetyl-L-lysyl-[protein] + NAD(+) + H2O = 2''-O-acetyl-ADP-D-ribose + nicotinamide + L-lysyl-[protein]; the Rhea xref of GO:0034979 (EC 2.3.1.286). processes: - preferred_term: protein deacetylation term: id: GO:0006476 label: protein deacetylation locations: - preferred_term: chromatin term: id: GO:0000785 label: chromatin role_description: >- Chromatin-bound sirtuin that deacetylates histone H3K9, H3K18 and H3K56 and non-histone targets, and removes long-chain fatty acyl groups; its separate mono-ADP-ribosyltransferase activity is a variant below. gocam_associations: - model: gomodel:61f34dd300000981 activity: gomodel:61f34dd300000981/61f34dd300000982 title: Regulation of gluconeogenesis by SIRT6, FOXO1 and KAT2A/GCN5 (Human) description: >- SIRT6 GO:0034979 NAD-dependent protein lysine deacetylase activity in the nucleus. evidence: - source_id: PMID:27568560 statement: >- SIRT6 has both deacetylase and mono-ADP-ribosyltransferase activity. supporting_text: SIRT6 catalyzes both deacetylation and mono-ADP ribosylation - id: sirt7_deacetylase label: SIRT7 NAD-dependent protein lysine deacetylase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SIRT7 term: id: UniProtKB:Q9NRC8 label: NAD-dependent protein deacetylase sirtuin-7 function: preferred_term: NAD-dependent protein lysine deacetylase activity term: id: GO:0034979 label: NAD-dependent protein lysine deacetylase activity substrates: - preferred_term: N6-acetyl-L-lysyl-[protein] term: id: CHEBI:61930 label: N(6)-acetyl-L-lysine residue - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) - preferred_term: water term: id: CHEBI:15377 label: water products: - preferred_term: L-lysyl-[protein] term: id: CHEBI:29969 label: L-lysinium residue - preferred_term: 2''-O-acetyl-ADP-D-ribose term: id: CHEBI:83767 label: 2''-O-acetyl-ADP-D-ribose(2-) - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide evidence: - source_id: RHEA:43636 statement: >- N(6)-acetyl-L-lysyl-[protein] + NAD(+) + H2O = 2''-O-acetyl-ADP-D-ribose + nicotinamide + L-lysyl-[protein]; the Rhea xref of GO:0034979 (EC 2.3.1.286). processes: - preferred_term: protein deacetylation term: id: GO:0006476 label: protein deacetylation locations: - preferred_term: nucleolus term: id: GO:0005730 label: nucleolus role_description: >- Nucleolar sirtuin; deacetylates H3K18 and the RNA polymerase I subunit PAF53, coupling rDNA transcription to stress. SIRT7 also carries desuccinylase and deglutarylase annotations (IDA). gocam_associations: - model: gomodel:65a1f4f800000029 activity: gomodel:65a1f4f800000029/65a1f4f800000083 title: USP49 and SIRT7 inhibition of AKT1 via PHLPP1-mediated dephosphorylation of AKT1 (Human) description: >- SIRT7 GO:0034979 NAD-dependent protein lysine deacetylase activity. evidence: - source_id: PMID:24207024 statement: >- SIRT7 deacetylates the Pol I subunit PAF53 at Lys373. supporting_text: Acetylation of PAF53 at lysine 373 by CBP and deacetylation by SIRT7 modulate the association of Pol I with DNA - id: sirtuin_other_deacylation label: NAD+-dependent removal of other lysine acyl groups (SIRT5 desuccinylation, SIRT4 delipoylation) module_type: REACTION description: >- Some sirtuins prefer acyl groups other than acetyl. The chemistry is the same: the acyl group is transferred to the ADP-ribose of NAD+, giving nicotinamide and 2''-O-acyl-ADP-ribose. annotons: - id: sirt5_desuccinylase label: SIRT5 protein-succinyllysine desuccinylase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SIRT5 term: id: UniProtKB:Q9NXA8 label: NAD-dependent protein deacylase sirtuin-5, mitochondrial function: preferred_term: protein-succinyllysine desuccinylase activity term: id: GO:0036055 label: protein-succinyllysine desuccinylase activity description: >- Desuccinylation is modelled as the representative reaction; SIRT5 equally demalonylates and deglutarylates (GO:0036054 and GO:0061697, both core in the SIRT5 gene review). substrates: - preferred_term: N6-succinyl-L-lysyl-[protein] term: id: CHEBI:87830 label: N(6)-succinyl-L-lysine(1-) residue - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) - preferred_term: water term: id: CHEBI:15377 label: water products: - preferred_term: L-lysyl-[protein] term: id: CHEBI:29969 label: L-lysinium residue - preferred_term: 2''-O-succinyl-ADP-D-ribose term: id: CHEBI:87832 label: 2''-O-succinyl-ADP-D-ribose(3-) - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide evidence: - source_id: RHEA:47668 statement: >- N(6)-succinyl-L-lysyl-[protein] + NAD(+) + H2O = 2''-O-succinyl-ADP-D-ribose + nicotinamide + L-lysyl-[protein]; the Rhea xref of GO:0036055. - source_id: RHEA:47672 statement: >- Demalonylation (GO:0036054): N(6)-malonyl-L-lysyl-[protein] + NAD(+) + H2O = 2''-O-malonyl-ADP-D-ribose + nicotinamide + L-lysyl-[protein]. - source_id: RHEA:47664 statement: >- Deglutarylation (GO:0061697): N(6)-glutaryl-L-lysyl-[protein] + NAD(+) + H2O = 2''-O-glutaryl-ADP-D-ribose + nicotinamide + L-lysyl-[protein]. processes: - preferred_term: protein desuccinylation term: id: GO:0036048 label: protein desuccinylation locations: - preferred_term: mitochondrial matrix term: id: GO:0005759 label: mitochondrial matrix role_description: >- Mitochondrial sirtuin with weak deacetylase but efficient desuccinylase, demalonylase and deglutarylase activity, set by Tyr102 and Arg105 in its acyl pocket. evidence: - source_id: PMID:22076378 statement: >- SIRT5 is an efficient lysine desuccinylase and demalonylase. supporting_text: is an efficient protein lysine desuccinylase and demalonylase in vitro - source_id: PMID:22076378 statement: >- The sirtuin mechanism transfers the acyl group to ADP-ribose, giving O-acyl-ADP-ribose. supporting_text: O-malonyl-ADPR (O-Ma-ADPR) or O-succinyl-ADPR (O-Su-ADPR) should be produced - id: sirt4_lipoamidase label: SIRT4 NAD-dependent protein lipoamidase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SIRT4 term: id: UniProtKB:Q9Y6E7 label: NAD-dependent protein lipoamidase sirtuin-4, mitochondrial function: preferred_term: NAD-dependent protein lipoamidase activity term: id: GO:0106419 label: NAD-dependent protein lipoamidase activity substrates: - preferred_term: N6-lipoyl-L-lysyl-[protein] term: id: CHEBI:83099 label: N(6)-[(R)-lipoyl]-L-lysine residue - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) - preferred_term: water term: id: CHEBI:15377 label: water products: - preferred_term: L-lysyl-[protein] term: id: CHEBI:29969 label: L-lysinium residue - preferred_term: 2''-O-lipoyl-ADP-D-ribose term: id: CHEBI:189572 label: 2''-O-lipoyl-ADP-D-ribose(2-) - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide evidence: - source_id: RHEA:63640 statement: >- N(6)-[(R)-lipoyl]-L-lysyl-[protein] + NAD(+) + H2O = 2''-O-lipoyl-ADP-D-ribose + nicotinamide + L-lysyl-[protein]; the Rhea xref of GO:0106419 (EC 2.3.1.313). locations: - preferred_term: mitochondrial matrix term: id: GO:0005759 label: mitochondrial matrix role_description: >- Mitochondrial sirtuin with no detectable deacetylase activity (NOT GO:0034979, IDA) that removes lipoyl groups from the DLAT E2 subunit of the pyruvate dehydrogenase complex, lowering PDH activity. evidence: - source_id: PMID:25525879 statement: >- SIRT4 delipoylates DLAT and inhibits the pyruvate dehydrogenase complex. supporting_text: glutamine stimulation induces endogenous SIRT4 lipoamidase activity, triggering a reduction in both DLAT lipoyl levels and PDH activity - id: sirtuin_mono_adp_ribosylation label: Sirtuin mono-ADP-ribosyltransferase activity (SIRT4, SIRT6) module_type: REACTION description: >- SIRT4 and SIRT6 also transfer the whole ADP-ribose of NAD+ to a protein acceptor, releasing nicotinamide. The physiological weight of this activity, relative to their deacylase activities, is less certain than for the PARPs. annotons: - id: sirt6_mart label: SIRT6 NAD+-protein-lysine ADP-ribosyltransferase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SIRT6 term: id: UniProtKB:Q8N6T7 label: NAD-dependent protein deacylase sirtuin-6 function: preferred_term: NAD+-protein-lysine ADP-ribosyltransferase activity term: id: GO:0140804 label: NAD+-protein-lysine ADP-ribosyltransferase activity substrates: - preferred_term: L-lysyl-[protein] term: id: CHEBI:29969 label: L-lysinium residue - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) products: - preferred_term: N6-(ADP-D-ribosyl)-L-lysyl-[protein] term: id: CHEBI:142515 label: 6-N-(ADP-D-ribosyl)-L-lysinium(1-) residue - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide - preferred_term: H+ term: id: CHEBI:15378 label: hydron evidence: - source_id: RHEA:58220 statement: >- L-lysyl-[protein] + NAD(+) = N(6)-(ADP-D-ribosyl)-L-lysyl-[protein] + nicotinamide + H(+); the Rhea xref of GO:0140804. locations: - preferred_term: site of DNA damage term: id: GO:0090734 label: site of DNA damage role_description: >- Under oxidative stress SIRT6 mono-ADP-ribosylates PARP1 on Lys521, stimulating PARP1 poly-ADP-ribosylation at DNA double-strand breaks. gocam_associations: - model: gomodel:622aace900000522 activity: gomodel:622aace900000522/622aace900000523 title: ADP-ribosyltransferase activity of SIRT6 and ADP-ribosylation of PARP1 during DNA repair (Human) description: >- SIRT6 GO:1990404 NAD+-protein mono-ADP-ribosyltransferase activity at DNA damage sites. evidence: - source_id: PMID:27568560 statement: >- SIRT6 mono-ADP-ribosylates PARP1 Lys521. supporting_text: SIRT6-mediated mono-ADP ribosylation of PARP1 on lysine 521 activates PARP1 poly-ADP ribosylation activity - id: sirt4_mart label: SIRT4 NAD+-protein-cysteine ADP-ribosyltransferase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SIRT4 term: id: UniProtKB:Q9Y6E7 label: NAD-dependent protein lipoamidase sirtuin-4, mitochondrial function: preferred_term: NAD+-protein-cysteine ADP-ribosyltransferase activity term: id: GO:0140803 label: NAD+-protein-cysteine ADP-ribosyltransferase activity substrates: - preferred_term: L-cysteinyl-[protein] term: id: CHEBI:29950 label: L-cysteine residue - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) products: - preferred_term: S-(ADP-D-ribosyl)-L-cysteinyl-[protein] term: id: CHEBI:140607 label: S-(ADP-D-ribosyl)-L-cysteine(2-) residue - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide - preferred_term: H+ term: id: CHEBI:15378 label: hydron evidence: - source_id: RHEA:56612 statement: >- L-cysteinyl-[protein] + NAD(+) = S-(ADP-D-ribosyl)-L-cysteinyl-[protein] + nicotinamide + H(+); the Rhea xref of GO:0140803. locations: - preferred_term: mitochondrial matrix term: id: GO:0005759 label: mitochondrial matrix role_description: >- SIRT4 ADP-ribosylates glutamate dehydrogenase and model acceptors, inhibiting GDH; the cysteine acceptor follows the GOA EXP annotation from the same study. evidence: - source_id: PMID:17715127 statement: >- SIRT4 is an ADP-ribosyltransferase rather than a deacetylase. supporting_text: SIRT4 exhibits no histone deacetylase activity but functions as an efficient ADP-ribosyltransferase on histones and bovine serum albumin evidence: - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0002581.yaml statement: >- The RGD record defines the sirtuin route and names nicotinamide as its inhibitory product. supporting_text: NAM, the product of the reaction, binds noncompetitively to sirtuins and inhibits them. - id: adp_ribosyltransferase_nad_consumption label: ADP-ribosyltransferase (PARP/ARTD) transfer of ADP-ribose from NAD+ to proteins module_type: MOLECULAR_FUNCTION description: >- Diphtheria-toxin-like ADP-ribosyltransferases (the PARP/ARTD family) cleave NAD+ and transfer its ADP-ribose to a protein acceptor (or to DNA ends), releasing nicotinamide. They divide by product into poly-ADP-ribose polymerases and mono-ADP-ribosyltransferases. variant_sets: - id: art_product label: ADP-ribosylation product axis: poly- versus mono-ADP-ribosylation selection: ONE_OR_MORE variants: - id: poly_adp_ribosylation label: Poly-ADP-ribose polymerases (PARP1, PARP2, TNKS, TNKS2) module_type: MOLECULAR_FUNCTION description: >- The few PARPs that keep the catalytic glutamate of the H-Y-E triad build ADP-ribose chains of up to about 200 units on an initiating ADP-ribose, consuming one NAD+ per unit. annotons: - id: parp1_ser_initiation label: PARP1 NAD+-protein-serine ADP-ribosyltransferase activity (with HPF1) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PARP1 term: id: UniProtKB:P09874 label: Poly [ADP-ribose] polymerase 1 function: preferred_term: NAD+-protein-serine ADP-ribosyltransferase activity term: id: GO:0140805 label: NAD+-protein-serine ADP-ribosyltransferase activity substrates: - preferred_term: L-seryl-[protein] term: id: CHEBI:29999 label: L-serine residue - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) products: - preferred_term: O-(ADP-D-ribosyl)-L-seryl-[protein] term: id: CHEBI:142556 label: O-(ADP-D-ribosyl)-L-serine(2-) residue - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide - preferred_term: H+ term: id: CHEBI:15378 label: hydron evidence: - source_id: RHEA:58232 statement: >- L-seryl-[protein] + NAD(+) = O-(ADP-D-ribosyl)-L-seryl-[protein] + nicotinamide + H(+); the Rhea xref of GO:0140805. locations: - preferred_term: site of DNA damage term: id: GO:0090734 label: site of DNA damage role_description: >- At DNA breaks, PARP1 bound to its cofactor HPF1 attaches the first ADP-ribose to serine residues of histones and of PARP1 itself; this is the main initiation site of DNA damage-induced ADP-ribosylation. gocam_associations: - model: gomodel:627d95ee00001943 activity: gomodel:627d95ee00001943/627d95ee00001951 title: Activation of PARP1 activity by HPF1 during DNA repair (Human) description: >- PARP1 GO:0140805 NAD+-protein-serine ADP-ribosyltransferase activity at a site of DNA damage. evidence: - source_id: PMID:28190768 statement: >- Serine ADP-ribosylation by PARP1 depends on HPF1. supporting_text: demonstrating that PARP-1 auto-ADPr on serine is also dependent on HPF1 - id: parp1_par label: PARP1 NAD+ poly-ADP-ribosyltransferase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PARP1 term: id: UniProtKB:P09874 label: Poly [ADP-ribose] polymerase 1 function: preferred_term: NAD+ poly-ADP-ribosyltransferase activity term: id: GO:0003950 label: NAD+ poly-ADP-ribosyltransferase activity description: >- NAD(+) + (ADP-D-ribosyl)n-acceptor = nicotinamide + (ADP-D-ribosyl)n+1-acceptor + H(+) (EC 2.4.2.30). Rhea has no reaction for chain elongation; the polymer is represented by CHEBI:142512. substrates: - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) products: - preferred_term: poly(ADP-ribose) term: id: CHEBI:142512 label: poly[(1''->2')-ADP-alpha-D-ribose] - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide - preferred_term: H+ term: id: CHEBI:15378 label: hydron processes: - preferred_term: protein poly-ADP-ribosylation term: id: GO:0070212 label: protein poly-ADP-ribosylation locations: - preferred_term: site of DNA damage term: id: GO:0090734 label: site of DNA damage role_description: >- DNA-break-activated PARP1 elongates and branches poly(ADP-ribose) chains; at maximal activation it can deplete cellular NAD+ by most of its pool, which is the basis of PARP1-SIRT1 competition for NAD+. gocam_associations: - model: gomodel:627d95ee00002067 activity: gomodel:627d95ee00002067/627d95ee00002084 title: Regulation of PARP2 activity by PARP1 and recruitment of APLF to DNA damage sites (Human) description: >- PARP1 GO:0003950 NAD+ poly-ADP-ribosyltransferase activity at a site of DNA damage; the project lead GO-CAM for PW:0002581. evidence: - source_id: PMID:7852410 statement: >- The catalytic Glu988 is required for poly-ADP-ribose elongation by PARP1. supporting_text: Glu988 may function in polymer elongation similarly to the toxins' active site glutamate - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0002581.yaml statement: >- RGD records the scale of PARP1-driven NAD+ depletion. supporting_text: The decrease in NAD concentration can reach 80% with maximal PARP1 activation. - id: parp2_par label: PARP2 NAD+ poly-ADP-ribosyltransferase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PARP2 term: id: UniProtKB:Q9UGN5 label: Poly [ADP-ribose] polymerase 2 function: preferred_term: NAD+ poly-ADP-ribosyltransferase activity term: id: GO:0003950 label: NAD+ poly-ADP-ribosyltransferase activity description: >- NAD(+) + (ADP-D-ribosyl)n-acceptor = nicotinamide + (ADP-D-ribosyl)n+1-acceptor + H(+) (EC 2.4.2.30). Rhea has no reaction for chain elongation; the polymer is represented by CHEBI:142512. substrates: - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) products: - preferred_term: poly(ADP-ribose) term: id: CHEBI:142512 label: poly[(1''->2')-ADP-alpha-D-ribose] - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide - preferred_term: H+ term: id: CHEBI:15378 label: hydron processes: - preferred_term: protein poly-ADP-ribosylation term: id: GO:0070212 label: protein poly-ADP-ribosylation locations: - preferred_term: site of DNA damage term: id: GO:0090734 label: site of DNA damage role_description: >- DNA-damage-activated PARP2 is stimulated by PARP1-made PAR and synthesises branched chains; with HPF1 it also initiates on serine (GO:0140805, IDA). gocam_associations: - model: gomodel:627d95ee00002067 activity: gomodel:627d95ee00002067/627d95ee00002077 title: Regulation of PARP2 activity by PARP1 and recruitment of APLF to DNA damage sites (Human) description: >- PARP2 GO:0003950 NAD+ poly-ADP-ribosyltransferase activity at a site of DNA damage. - model: gomodel:627d95ee00002030 activity: gomodel:627d95ee00002030/627d95ee00002040 title: Activation of PARP2 activity by HPF1 during DNA repair (Human) description: >- PARP2 GO:0140805 NAD+-protein-serine ADP-ribosyltransferase activity with HPF1. evidence: - source_id: PMID:30104678 statement: >- PARP2 synthesises branched PAR after activation by PAR. supporting_text: PARP2 is preferentially activated by PAR and subsequently catalyzes branched PAR chain synthesis - id: tnks_par label: Tankyrase-1 (TNKS) NAD+ poly-ADP-ribosyltransferase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: TNKS term: id: UniProtKB:O95271 label: Poly [ADP-ribose] polymerase tankyrase-1 function: preferred_term: NAD+ poly-ADP-ribosyltransferase activity term: id: GO:0003950 label: NAD+ poly-ADP-ribosyltransferase activity description: >- NAD(+) + (ADP-D-ribosyl)n-acceptor = nicotinamide + (ADP-D-ribosyl)n+1-acceptor + H(+) (EC 2.4.2.30). Rhea has no reaction for chain elongation; the polymer is represented by CHEBI:142512. substrates: - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) products: - preferred_term: poly(ADP-ribose) term: id: CHEBI:142512 label: poly[(1''->2')-ADP-alpha-D-ribose] - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide - preferred_term: H+ term: id: CHEBI:15378 label: hydron processes: - preferred_term: protein poly-ADP-ribosylation term: id: GO:0070212 label: protein poly-ADP-ribosylation locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Ankyrin-repeat PARP that poly-ADP-ribosylates TRF1, AXIN and itself; the PAR it adds is read by RNF146 and directs targets to proteasomal degradation. evidence: - source_id: PMID:9822378 statement: >- Recombinant tankyrase has PARP activity toward TRF1 and itself. supporting_text: Recombinant tankyrase was found to have PARP activity in vitro, with both TRF1 and tankyrase functioning as acceptors for adenosine diphosphate (ADP)-ribosylation - id: tnks2_par label: Tankyrase-2 (TNKS2) NAD+ poly-ADP-ribosyltransferase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: TNKS2 term: id: UniProtKB:Q9H2K2 label: Poly [ADP-ribose] polymerase tankyrase-2 function: preferred_term: NAD+ poly-ADP-ribosyltransferase activity term: id: GO:0003950 label: NAD+ poly-ADP-ribosyltransferase activity description: >- NAD(+) + (ADP-D-ribosyl)n-acceptor = nicotinamide + (ADP-D-ribosyl)n+1-acceptor + H(+) (EC 2.4.2.30). Rhea has no reaction for chain elongation; the polymer is represented by CHEBI:142512. substrates: - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) products: - preferred_term: poly(ADP-ribose) term: id: CHEBI:142512 label: poly[(1''->2')-ADP-alpha-D-ribose] - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide - preferred_term: H+ term: id: CHEBI:15378 label: hydron processes: - preferred_term: protein poly-ADP-ribosylation term: id: GO:0070212 label: protein poly-ADP-ribosylation locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Tankyrase-1 paralogue with the same substrate range and partial redundancy. evidence: - source_id: PMID:11739745 statement: >- Recombinant tankyrase 2 poly-ADP-ribosylates itself and TRF1. supporting_text: Tankyrase 2 poly(ADP-ribosyl)ated itself and TRF1 - id: mono_adp_ribosylation label: Mono-ADP-ribosyltransferases (PARP3, PARP4, PARP6, PARP8, PARP10-12, PARP14-16, TIPARP) module_type: MOLECULAR_FUNCTION description: >- Most PARPs lack the catalytic glutamate and transfer a single ADP-ribose to an acceptor residue (glutamate, aspartate, cysteine, lysine or serine), consuming one NAD+ per modification. annotons: - id: parp3_mart label: PARP3 NAD+-protein mono-ADP-ribosyltransferase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PARP3 term: id: UniProtKB:Q9Y6F1 label: Protein mono-ADP-ribosyltransferase PARP3 function: preferred_term: NAD+-protein mono-ADP-ribosyltransferase activity term: id: GO:1990404 label: NAD+-protein mono-ADP-ribosyltransferase activity substrates: - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) products: - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide locations: - preferred_term: nucleus term: id: GO:0005634 label: nucleus role_description: >- DNA-break-associated mono-ADP-ribosyltransferase that modifies histone H1 and itself and, with PARP1, acts in double-strand break repair. evidence: - source_id: PMID:20064938 statement: >- PARP3 is a mono-ADP-ribosylase, unlike PARP1 and PARP2. supporting_text: PARP-3 is not activated upon binding to DNA and is a mono-ADP-ribosylase, in contrast to PARP-1 and PARP-2 - id: parp4_mart label: PARP4 NAD+-protein mono-ADP-ribosyltransferase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PARP4 term: id: UniProtKB:Q9UKK3 label: Protein mono-ADP-ribosyltransferase PARP4 function: preferred_term: NAD+-protein mono-ADP-ribosyltransferase activity term: id: GO:1990404 label: NAD+-protein mono-ADP-ribosyltransferase activity substrates: - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) products: - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Vault-associated PARP (VPARP); mono-ADP-ribosyltransferase activity shown in the family-wide assay (IDA). Its physiological substrates are poorly defined. evidence: - source_id: PMID:25043379 statement: >- Family-wide assay of PARP products, the IDA source for PARP4 GO:1990404. supporting_text: Here we show that the majority of PARPs generate MAR, not PAR, and demonstrate that the H-Y-E motif is not the sole indicator of PARP activity. - id: parp6_mart label: PARP6 NAD+-protein-cysteine ADP-ribosyltransferase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PARP6 term: id: UniProtKB:Q2NL67 label: Protein mono-ADP-ribosyltransferase PARP6 function: preferred_term: NAD+-protein-cysteine ADP-ribosyltransferase activity term: id: GO:0140803 label: NAD+-protein-cysteine ADP-ribosyltransferase activity substrates: - preferred_term: L-cysteinyl-[protein] term: id: CHEBI:29950 label: L-cysteine residue - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) products: - preferred_term: S-(ADP-D-ribosyl)-L-cysteinyl-[protein] term: id: CHEBI:140607 label: S-(ADP-D-ribosyl)-L-cysteine(2-) residue - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide - preferred_term: H+ term: id: CHEBI:15378 label: hydron evidence: - source_id: RHEA:56612 statement: >- L-cysteinyl-[protein] + NAD(+) = S-(ADP-D-ribosyl)-L-cysteinyl-[protein] + nicotinamide + H(+); the Rhea xref of GO:0140803. role_description: >- Mono-ADP-ribosylates cysteine (and aspartate) residues in the family-wide automodification assay (IDA). evidence: - source_id: PMID:25043379 statement: >- Family-wide assay identifying cysteine as an ADP-ribose acceptor, the IDA source for PARP6 GO:0140803. supporting_text: Here we show that the majority of PARPs generate MAR, not PAR, and demonstrate that the H-Y-E motif is not the sole indicator of PARP activity. - id: parp8_mart label: PARP8 NAD+-protein mono-ADP-ribosyltransferase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PARP8 term: id: UniProtKB:Q8N3A8 label: Protein mono-ADP-ribosyltransferase PARP8 function: preferred_term: NAD+-protein mono-ADP-ribosyltransferase activity term: id: GO:1990404 label: NAD+-protein mono-ADP-ribosyltransferase activity substrates: - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) products: - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide role_description: >- PARP6 paralogue; mono-ADP-ribosyltransferase activity with cysteine acceptors (GO:0140803, EXP). evidence: - source_id: PMID:25043379 statement: >- Family-wide assay, the IDA/EXP source for PARP8 mono-ADP-ribosyltransferase activity. supporting_text: Here we show that the majority of PARPs generate MAR, not PAR, and demonstrate that the H-Y-E motif is not the sole indicator of PARP activity. - id: parp10_mart label: PARP10 NAD+-protein-glutamate ADP-ribosyltransferase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PARP10 term: id: UniProtKB:Q53GL7 label: Protein mono-ADP-ribosyltransferase PARP10 function: preferred_term: NAD+-protein-glutamate ADP-ribosyltransferase activity term: id: GO:0140807 label: NAD+-protein-glutamate ADP-ribosyltransferase activity substrates: - preferred_term: L-glutamyl-[protein] term: id: CHEBI:29973 label: L-glutamate residue - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) products: - preferred_term: 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein] term: id: CHEBI:142540 label: 5-O-(ADP-D-ribosyl)-L-glutamate(2-) residue - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide evidence: - source_id: RHEA:58224 statement: >- L-glutamyl-[protein] + NAD(+) = 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein] + nicotinamide; the Rhea xref of GO:0140807. role_description: >- Prototype mono-ART of the family: lacking the catalytic glutamate, it uses substrate-assisted catalysis to mono-ADP-ribosylate acidic residues (for example of GSK3B), a modification reversed by MACROD1, MACROD2 and OARD1. evidence: - source_id: PMID:18851833 statement: >- PARP10 is a transferase rather than a polymerase. supporting_text: PARP10, in contrast to PARP1, lacks the catalytic glutamate and has transferase rather than polymerase activity - source_id: PMID:18851833 statement: >- PARP10 modifies acidic residues. supporting_text: PARP10 also modifies acidic residues - id: parp11_mart label: PARP11 NAD+-protein mono-ADP-ribosyltransferase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PARP11 term: id: UniProtKB:Q9NR21 label: Protein mono-ADP-ribosyltransferase PARP11 function: preferred_term: NAD+-protein mono-ADP-ribosyltransferase activity term: id: GO:1990404 label: NAD+-protein mono-ADP-ribosyltransferase activity substrates: - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) products: - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide role_description: >- Mono-ADP-ribosyltransferase with glutamate, aspartate, lysine and cysteine acceptors in the family-wide assay (EXP). evidence: - source_id: PMID:25043379 statement: >- Family-wide assay, the IDA/EXP source for PARP11 mono-ADP-ribosyltransferase activity. supporting_text: Here we show that the majority of PARPs generate MAR, not PAR, and demonstrate that the H-Y-E motif is not the sole indicator of PARP activity. - id: parp12_mart label: PARP12 NAD+-protein mono-ADP-ribosyltransferase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PARP12 term: id: UniProtKB:Q9H0J9 label: Protein mono-ADP-ribosyltransferase PARP12 function: preferred_term: NAD+-protein mono-ADP-ribosyltransferase activity term: id: GO:1990404 label: NAD+-protein mono-ADP-ribosyltransferase activity substrates: - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) products: - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide role_description: >- Interferon-induced mono-ART; at the trans-Golgi network it mono-ADP-ribosylates GOLGA1 to support E-cadherin transport. gocam_associations: - model: gomodel:67c10cc400005330 activity: gomodel:67c10cc400005330/67c10cc400005331 title: PARP12 activated GOLGA1 activity toward E-cadherin (Human) description: >- PARP12 GO:1990404 NAD+-protein mono-ADP-ribosyltransferase activity at the trans-Golgi network. evidence: - source_id: PMID:25043379 statement: >- Family-wide assay, the IDA source for PARP12 GO:1990404. supporting_text: Here we show that the majority of PARPs generate MAR, not PAR, and demonstrate that the H-Y-E motif is not the sole indicator of PARP activity. - id: parp14_mart label: PARP14 NAD+-protein-glutamate ADP-ribosyltransferase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PARP14 term: id: UniProtKB:Q460N5 label: Protein mono-ADP-ribosyltransferase PARP14 function: preferred_term: NAD+-protein-glutamate ADP-ribosyltransferase activity term: id: GO:0140807 label: NAD+-protein-glutamate ADP-ribosyltransferase activity substrates: - preferred_term: L-glutamyl-[protein] term: id: CHEBI:29973 label: L-glutamate residue - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) products: - preferred_term: 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein] term: id: CHEBI:142540 label: 5-O-(ADP-D-ribosyl)-L-glutamate(2-) residue - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide evidence: - source_id: RHEA:58224 statement: >- L-glutamyl-[protein] + NAD(+) = 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein] + nicotinamide; the Rhea xref of GO:0140807. role_description: >- Macrodomain-containing mono-ART that mono-ADP-ribosylates STAT1 on Glu657 and Glu705 and regulates macrophage activation; PARP9 suppresses this activity. evidence: - source_id: PMID:27796300 statement: >- PARP14 mono-ADP-ribosylates STAT1. supporting_text: ADP-ribosylation assays demonstrated that PARP14 has the ability to mono-ADP-ribosylate STAT1 - id: parp15_mart label: PARP15 NAD+-protein mono-ADP-ribosyltransferase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PARP15 term: id: UniProtKB:Q460N3 label: Protein mono-ADP-ribosyltransferase PARP15 function: preferred_term: NAD+-protein mono-ADP-ribosyltransferase activity term: id: GO:1990404 label: NAD+-protein mono-ADP-ribosyltransferase activity substrates: - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) products: - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide role_description: >- Macrodomain-containing PARP14 paralogue; mono-ADP-ribosyltransferase activity in the family-wide assay (IDA). evidence: - source_id: PMID:25043379 statement: >- Family-wide assay, the IDA source for PARP15 GO:1990404. supporting_text: Here we show that the majority of PARPs generate MAR, not PAR, and demonstrate that the H-Y-E motif is not the sole indicator of PARP activity. - id: parp16_mart label: PARP16 NAD+-protein-glutamate ADP-ribosyltransferase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PARP16 term: id: UniProtKB:Q8N5Y8 label: Protein mono-ADP-ribosyltransferase PARP16 function: preferred_term: NAD+-protein-glutamate ADP-ribosyltransferase activity term: id: GO:0140807 label: NAD+-protein-glutamate ADP-ribosyltransferase activity substrates: - preferred_term: L-glutamyl-[protein] term: id: CHEBI:29973 label: L-glutamate residue - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) products: - preferred_term: 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein] term: id: CHEBI:142540 label: 5-O-(ADP-D-ribosyl)-L-glutamate(2-) residue - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide evidence: - source_id: RHEA:58224 statement: >- L-glutamyl-[protein] + NAD(+) = 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein] + nicotinamide; the Rhea xref of GO:0140807. locations: - preferred_term: endoplasmic reticulum membrane term: id: GO:0005789 label: endoplasmic reticulum membrane role_description: >- Tail-anchored ER-membrane mono-ART that modifies ribosomal proteins on glutamate/aspartate, limiting translation; it draws on cytosolic NAD+ made by NMNAT2. gocam_associations: - model: gomodel:62900b6400000022 activity: gomodel:62900b6400000022/62900b6400000023 title: Mono-ADP-ribosylation of ribosome subunits by PARP16 (Human) description: >- PARP16 GO:0140807 NAD+-protein-glutamate ADP-ribosyltransferase activity on ribosomal proteins. evidence: - source_id: PMID:34314702 statement: >- PARP16 is a mono-ART that MARylates ribosomal proteins, supported by NMNAT2-made NAD+. supporting_text: NMNAT-2 supports the catalytic activity of the mono(ADP-ribosyl) transferase (MART) PARP-16, which mono(ADP-ribosyl)ates (MARylates) ribosomal proteins - id: tiparp_mart label: TIPARP NAD+-protein mono-ADP-ribosyltransferase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: TIPARP term: id: UniProtKB:Q7Z3E1 label: Protein mono-ADP-ribosyltransferase TIPARP function: preferred_term: NAD+-protein mono-ADP-ribosyltransferase activity term: id: GO:1990404 label: NAD+-protein mono-ADP-ribosyltransferase activity substrates: - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) products: - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide locations: - preferred_term: nucleus term: id: GO:0005634 label: nucleus role_description: >- PARP7; aryl hydrocarbon receptor target gene whose mono-ART activity represses AHR transactivation in a negative feedback loop. evidence: - source_id: PMID:23275542 statement: >- TIPARP is a mono-ADP-ribosyltransferase. supporting_text: is a mono-ADP-ribosyltransferase and repressor of aryl hydrocarbon receptor transactivation evidence: - source_id: PMID:25043379 statement: >- PAR versus MAR products were assigned experimentally across the family; most PARPs make MAR, which sets this variant split. supporting_text: Here we show that the majority of PARPs generate MAR, not PAR, and demonstrate that the H-Y-E motif is not the sole indicator of PARP activity. - id: nad_glycohydrolase_cyclase label: NAD+ glycohydrolase / ADP-ribosyl cyclase (CD38, BST1) module_type: MOLECULAR_FUNCTION description: >- The ectoenzymes CD38 and BST1 (CD157) cleave NAD+ to nicotinamide and either cyclise the ADP-ribose to cyclic ADP-ribose (cADPR) or, far more often, hydrolyse it to ADP-ribose; they also hydrolyse cADPR to ADP-ribose. CD38 hydrolyses roughly 100 NAD+ for each cADPR made and is a dominant NAD+ consumer in many mammalian tissues. cADPR acts as a calcium-mobilising messenger at ryanodine receptors. variant_sets: - id: adp_ribosyl_cyclase label: ADP-ribosyl cyclase paralogue axis: paralogue selection: ONE_OR_MORE variants: - id: cd38_variant label: CD38 module_type: REACTION annotons: - id: cd38_cyclase label: CD38 NAD+ nucleosidase activity, cyclic ADP-ribose generating participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CD38 term: id: UniProtKB:P28907 label: ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 function: preferred_term: NAD+ nucleosidase activity, cyclic ADP-ribose generating term: id: GO:0061809 label: NAD+ nucleosidase activity, cyclic ADP-ribose generating substrates: - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) - preferred_term: water term: id: CHEBI:15377 label: water products: - preferred_term: cyclic ADP-ribose term: id: CHEBI:73672 label: cyclic ADP-beta-D-ribose(2-) - preferred_term: ADP-D-ribose term: id: CHEBI:57967 label: ADP-D-ribose(2-) - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide - preferred_term: H+ term: id: CHEBI:15378 label: hydron evidence: - source_id: RHEA:38611 statement: >- NAD(+) = cyclic ADP-beta-D-ribose + nicotinamide + H(+); a Rhea xref of GO:0061809. - source_id: RHEA:38615 statement: >- cyclic ADP-beta-D-ribose + H2O = ADP-D-ribose; the second Rhea xref of GO:0061809 (cADPR hydrolase). - source_id: RHEA:16301 statement: >- NAD(+) + H2O = ADP-D-ribose + nicotinamide + H(+) (EC 3.2.2.6); the predominant NAD+ glycohydrolase reaction. processes: - preferred_term: NAD+ catabolic process term: id: GO:0019677 label: NAD+ catabolic process locations: - preferred_term: external side of plasma membrane term: id: GO:0009897 label: external side of plasma membrane role_description: >- Type II transmembrane glycoprotein of leukocytes and many other cells whose C-terminal catalytic domain usually faces outward, though catalytically active intracellular forms exist. It makes cADPR and ADP-ribose and hydrolyses cADPR; under acidic conditions it can also make NAADP (not modelled). evidence: - source_id: PMID:8253715 statement: >- Membranes expressing human CD38 convert NAD+ to cADPR and ADP-ribose. supporting_text: the formation of cADPR was observed in addition to the ADP-ribose (ADPR) formation - source_id: PMID:8253715 statement: >- CD38 hydrolyses cADPR to ADP-ribose. supporting_text: When the plasma membrane fraction was incubated with cADPR, cADPR was converted to ADPR stoichiometrically - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0002581.yaml statement: >- RGD records the high NAD+ consumption by CD38. supporting_text: Of note is the high NAD consumption by Cd38, with hydrolysis of ~100 NAD molecule to yield one cADPR molecule. - id: bst1_variant label: BST1 (CD157) module_type: REACTION annotons: - id: bst1_cyclase label: BST1 NAD+ nucleosidase activity, cyclic ADP-ribose generating participant: selector_type: GENE_PRODUCT gene_product: preferred_term: BST1 term: id: UniProtKB:Q10588 label: ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 2 function: preferred_term: NAD+ nucleosidase activity, cyclic ADP-ribose generating term: id: GO:0061809 label: NAD+ nucleosidase activity, cyclic ADP-ribose generating substrates: - preferred_term: NAD+ term: id: CHEBI:57540 label: NAD(1-) - preferred_term: water term: id: CHEBI:15377 label: water products: - preferred_term: cyclic ADP-ribose term: id: CHEBI:73672 label: cyclic ADP-beta-D-ribose(2-) - preferred_term: ADP-D-ribose term: id: CHEBI:57967 label: ADP-D-ribose(2-) - preferred_term: nicotinamide term: id: CHEBI:17154 label: nicotinamide - preferred_term: H+ term: id: CHEBI:15378 label: hydron evidence: - source_id: RHEA:38611 statement: >- NAD(+) = cyclic ADP-beta-D-ribose + nicotinamide + H(+); a Rhea xref of GO:0061809. - source_id: RHEA:38615 statement: >- cyclic ADP-beta-D-ribose + H2O = ADP-D-ribose; the second Rhea xref of GO:0061809 (cADPR hydrolase). - source_id: RHEA:16301 statement: >- NAD(+) + H2O = ADP-D-ribose + nicotinamide + H(+) (EC 3.2.2.6); the predominant NAD+ glycohydrolase reaction. processes: - preferred_term: NAD+ catabolic process term: id: GO:0019677 label: NAD+ catabolic process locations: - preferred_term: external side of plasma membrane term: id: GO:0009897 label: external side of plasma membrane role_description: >- GPI-anchored CD38 paralogue of bone marrow stromal and myeloid cells, with ADP-ribosyl cyclase and cADPR hydrolase activity; its catalytic efficiency is much lower than that of CD38. evidence: - source_id: PMID:7805847 statement: >- Soluble human BST1 has ADP-ribosyl cyclase and cADPR hydrolase activity. supporting_text: purified soluble BST-1 displays both ADP ribosyl cyclase and cADPR hydrolase activities evidence: - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0002581.yaml statement: >- The RGD record defines the three NAD+-utilisation routes modelled as the variants. supporting_text: 'There are three pathways of NAD utilization: the sirtuin mediated pathway and the ADP ribosylation pathways - mono and poly-ribosylation, and cyclic ribosylation.' - order: 2 role: reversal of protein ADP-ribosylation node: id: adp_ribose_removal label: Hydrolytic removal of protein-linked ADP-ribose module_type: MOLECULAR_FUNCTION description: >- ADP-ribosylation is reversible. PAR glycohydrolase (PARG) hydrolyses the ribose-ribose bonds of poly(ADP-ribose), releasing free ADP-ribose, but cannot remove the proximal ADP-ribose attached to the protein. The macrodomain hydrolases MACROD1, MACROD2 and OARD1 (TARG1) remove mono-ADP-ribose from glutamate and aspartate residues, again releasing ADP-ribose. ADP-ribose made here and by CD38/BST1 is cleaved further by NUDIX hydrolases, outside this module. variant_sets: - id: eraser label: ADP-ribose eraser axis: linkage hydrolysed (PAR glycosidic bond versus protein-proximal ester bond) selection: ONE_OR_MORE variants: - id: parg_variant label: 'PARG: poly(ADP-ribose) chain hydrolysis' module_type: REACTION annotons: - id: parg_glycohydrolase label: PARG poly(ADP-ribose) glycohydrolase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PARG term: id: UniProtKB:Q86W56 label: Poly(ADP-ribose) glycohydrolase function: preferred_term: poly(ADP-ribose) glycohydrolase activity term: id: GO:0004649 label: poly(ADP-ribose) glycohydrolase activity substrates: - preferred_term: poly(ADP-ribose) term: id: CHEBI:142512 label: poly[(1''->2')-ADP-alpha-D-ribose] - preferred_term: water term: id: CHEBI:15377 label: water products: - preferred_term: ADP-D-ribose term: id: CHEBI:57967 label: ADP-D-ribose(2-) evidence: - source_id: RHEA:52216 statement: >- [(1''->2')-ADP-alpha-D-ribose](n) + H2O = [(1''->2')-ADP-alpha-D-ribose](n-1) + ADP-D-ribose; the Rhea xref of GO:0004649 (EC 3.2.1.143). processes: - preferred_term: protein de-ADP-ribosylation term: id: GO:0051725 label: protein de-ADP-ribosylation locations: - preferred_term: nucleus term: id: GO:0005634 label: nucleus role_description: >- The only enzyme that hydrolyses PAR chains efficiently, by exo- and endoglycosidic cleavage; it turns over PAR made by PARP1 and PARP2 within minutes of DNA damage. evidence: - source_id: PMID:23481255 statement: >- PARG hydrolyses PAR chains but not the protein-proximal ADP-ribose. supporting_text: PARG is unable to cleave the mono(ADP-ribose) unit directly linked to the protein - id: macrodomain_mono_hydrolase_variant label: Macrodomain mono-ADP-ribosyl hydrolases (MACROD1, MACROD2, OARD1) module_type: MOLECULAR_FUNCTION annotons: - id: macrod1_hydrolase label: MACROD1 ADP-ribosylglutamate-[protein] hydrolase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: MACROD1 term: id: UniProtKB:Q9BQ69 label: ADP-ribose glycohydrolase MACROD1 function: preferred_term: ADP-ribosylglutamate-[protein] hydrolase activity term: id: GO:0140293 label: ADP-ribosylglutamate-[protein] hydrolase activity substrates: - preferred_term: 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein] term: id: CHEBI:142540 label: 5-O-(ADP-D-ribosyl)-L-glutamate(2-) residue - preferred_term: water term: id: CHEBI:15377 label: water products: - preferred_term: L-glutamyl-[protein] term: id: CHEBI:29973 label: L-glutamate residue - preferred_term: ADP-D-ribose term: id: CHEBI:57967 label: ADP-D-ribose(2-) - preferred_term: H+ term: id: CHEBI:15378 label: hydron evidence: - source_id: RHEA:58248 statement: >- 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein] + H2O = L-glutamyl-[protein] + ADP-D-ribose + H(+); the Rhea xref of GO:0140293. - source_id: RHEA:54428 statement: >- 4-O-(ADP-D-ribosyl)-L-aspartyl-[protein] + H2O = L-aspartyl-[protein] + ADP-D-ribose + H(+); the aspartyl counterpart. processes: - preferred_term: peptidyl-glutamate ADP-deribosylation term: id: GO:0140291 label: peptidyl-glutamate ADP-deribosylation locations: - preferred_term: mitochondrial matrix term: id: GO:0005759 label: mitochondrial matrix role_description: >- Mitochondrially enriched macrodomain hydrolase that removes mono-ADP-ribose from acidic residues; it also deacetylates O-acetyl-ADP-ribose (GO:0019213, IDA). evidence: - source_id: PMID:23474714 statement: >- MACROD1, MACROD2 and C6orf130 (OARD1) reverse ARTD10 mono-ADP-ribosylation. supporting_text: ARTD10-modified targets are substrates for the macrodomain proteins MacroD1, MacroD2 and C6orf130 from Homo sapiens - id: macrod2_hydrolase label: MACROD2 ADP-ribosylglutamate-[protein] hydrolase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: MACROD2 term: id: UniProtKB:A1Z1Q3 label: ADP-ribose glycohydrolase MACROD2 function: preferred_term: ADP-ribosylglutamate-[protein] hydrolase activity term: id: GO:0140293 label: ADP-ribosylglutamate-[protein] hydrolase activity substrates: - preferred_term: 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein] term: id: CHEBI:142540 label: 5-O-(ADP-D-ribosyl)-L-glutamate(2-) residue - preferred_term: water term: id: CHEBI:15377 label: water products: - preferred_term: L-glutamyl-[protein] term: id: CHEBI:29973 label: L-glutamate residue - preferred_term: ADP-D-ribose term: id: CHEBI:57967 label: ADP-D-ribose(2-) - preferred_term: H+ term: id: CHEBI:15378 label: hydron evidence: - source_id: RHEA:58248 statement: >- 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein] + H2O = L-glutamyl-[protein] + ADP-D-ribose + H(+); the Rhea xref of GO:0140293. processes: - preferred_term: peptidyl-glutamate ADP-deribosylation term: id: GO:0140291 label: peptidyl-glutamate ADP-deribosylation role_description: >- MACROD1 paralogue; reverses PARP10 mono-ADP-ribosylation of GSK3B, restoring kinase activity. evidence: - source_id: PMID:23474714 statement: >- MACROD2 reverses PARP10-mediated inhibition of GSK3B. supporting_text: MacroD2 reversed the ARTD10-catalyzed, mono-ADP-ribose-mediated inhibition of glycogen synthase kinase 3β (GSK3β) in vitro and in cells - id: oard1_hydrolase label: OARD1 (TARG1) ADP-ribosylglutamate-[protein] hydrolase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: OARD1 term: id: UniProtKB:Q9Y530 label: ADP-ribose glycohydrolase OARD1 function: preferred_term: ADP-ribosylglutamate-[protein] hydrolase activity term: id: GO:0140293 label: ADP-ribosylglutamate-[protein] hydrolase activity substrates: - preferred_term: 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein] term: id: CHEBI:142540 label: 5-O-(ADP-D-ribosyl)-L-glutamate(2-) residue - preferred_term: water term: id: CHEBI:15377 label: water products: - preferred_term: L-glutamyl-[protein] term: id: CHEBI:29973 label: L-glutamate residue - preferred_term: ADP-D-ribose term: id: CHEBI:57967 label: ADP-D-ribose(2-) - preferred_term: H+ term: id: CHEBI:15378 label: hydron evidence: - source_id: RHEA:58248 statement: >- 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein] + H2O = L-glutamyl-[protein] + ADP-D-ribose + H(+); the Rhea xref of GO:0140293. processes: - preferred_term: peptidyl-glutamate ADP-deribosylation term: id: GO:0140291 label: peptidyl-glutamate ADP-deribosylation role_description: >- Terminal ADP-ribose protein glycohydrolase that removes the protein-proximal ADP-ribose left by PARG on glutamate residues; its loss causes neurodegeneration in humans. It also deacetylates O-acetyl-ADP-ribose (GO:0061463, IDA). evidence: - source_id: PMID:23481255 statement: >- C6orf130/TARG1 (OARD1) removes mono-ADP-ribose from glutamate residues. supporting_text: identify C6orf130 as a PARP-interacting protein that removes mono(ADP-ribosyl)ation on glutamate amino acid residues in PARP-modified proteins evidence: - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0002581.yaml statement: >- RGD names PARG, MACROD1, MACROD2 and OARD1 as the erasers of the pathway. supporting_text: Erasers, such PAR glycohydrolase, the Macro1, Macro2 and Oard1 (TARG1) glycohydrolases, all have a macrodomain fold to bind the modified protein and catalyze ADP-ribosyl hydrolysis. - order: 3 role: recycling of released nicotinamide to NAD+ optional: true node: id: nicotinamide_salvage_to_nad label: NAMPT salvage of released nicotinamide back to NAD+ description: >- Included by reference to the NAMPT/NMN realization of the NAD+ biosynthesis and salvage module: nicotinamide released by every consumer above is phosphoribosylated by NAMPT to NMN and adenylylated by NMNAT to NAD+, closing the cycle. module_ref: nad_biosynthesis_salvage#nmn_to_nad_realization connections: - source: adp_ribosyltransferase_nad_consumption target: adp_ribose_removal connection_type: PROVIDES_INPUT_FOR description: Poly- and mono-ADP-ribosylated proteins made by the PARPs are the substrates of PARG and the macrodomain hydrolases. chaining_status: NOT_APPLICABLE chaining_note: The intermediates are protein-linked ADP-ribose (CHEBI:142512, CHEBI:142540), not CoA thioesters. - source: nad_consuming_reactions target: nicotinamide_salvage_to_nad connection_type: PROVIDES_INPUT_FOR description: Nicotinamide (CHEBI:17154), the common product of every consumer reaction, is the NAMPT substrate in the referenced salvage route. chaining_status: NOT_APPLICABLE chaining_note: Nicotinamide continuity is not a CoA-carrier link. gocam_associations: - model: gomodel:627d95ee00002067 title: Regulation of PARP2 activity by PARP1 and recruitment of APLF to DNA damage sites (Human) description: >- Best-overlap GO-CAM for PW:0002581 (PARP1, PARP2, APLF). Its PARP1 and PARP2 poly-ADP-ribosyltransferase activities are linked on the annotons; the APLF PAR-reader and histone-chaperone activities and MACROH2A1 are context (see notes).