ALAD encodes delta-aminolevulinic acid dehydratase (ALADH), also known as porphobilinogen synthase (PBGS; EC 4.2.1.24). It catalyzes the second step of heme biosynthesis: the asymmetric condensation of two molecules of 5-aminolevulinate (ALA) to form the monopyrrole porphobilinogen (PBG), releasing two water molecules. This is the first pyrrole-forming reaction and commits the pathway toward all tetrapyrroles (heme, and in other organisms chlorophyll and cobalamin). The enzyme is a cytosolic, zinc-dependent metalloenzyme that assembles as a homo-octamer (the high-activity form), binding up to eight Zn2+ per octamer with four required for catalysis; it exists in a morpheein-type equilibrium between the active octamer and a low-activity hexamer, with a magnesium ion promoting octamer assembly. ALAD activity is potently inhibited by divalent lead, which partially displaces the catalytic zinc, making the enzyme the classic biochemical biomarker and principal molecular target of lead poisoning. Loss-of-function variants that shift the quaternary equilibrium toward the hexamer cause the rare autosomal-recessive ALAD-deficiency porphyria (Doss porphyria / acute hepatic porphyria). Independently of its catalytic role, the protein has been characterized as an endogenous proteasome inhibitor (CF-2), an ATP-stabilized component associated with the 26S proteasome, an example of gene sharing/moonlighting.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006783 heme biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred involvement in heme biosynthesis. ALAD catalyzes the second, committed pyrrole-forming step of the heme pathway, so this is a core biological process. Reason: PAINT IBA (GO_REF:0000033) propagated within PANTHER family PTHR11458 (delta-aminolevulinic acid dehydratase); human ALAD is a member of the family whose ancestral function is the porphobilinogen-forming step of tetrapyrrole synthesis, and the human enzyme is experimentally characterized as the second enzyme of heme biosynthesis. Core biological process. Supporting Evidence: PMID:3463993 Two cDNAs encoding human delta-aminolevulinate dehydratase (ALA-D; porphobilinogen synthase; EC 4.2.1.24), the second enzyme in the heme biosynthetic pathway file:human/ALAD/ALAD-uniprot.txt PATHWAY: Porphyrin-containing compound metabolism; protoporphyrin-IX biosynthesis; coproporphyrinogen-III from 5-aminolevulinate: step 1/4. file:human/ALAD/ALAD-uniprot.txt PANTHER; PTHR11458; DELTA-AMINOLEVULINIC ACID DEHYDRATASE; 1. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred cytosolic localization. The cytosolic steps of heme biosynthesis, including the ALAD reaction, occur in the cytosol. Reason: Consistent with the UniProt-curated subcellular location (Cytoplasm, cytosol) and with Reactome, which places the ALAD-catalyzed step among the cytosolic heme-synthesis steps. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol Reactome:R-HSA-189451 The next four steps take place in the cytosol. file:human/ALAD/ALAD-uniprot.txt PANTHER; PTHR11458; DELTA-AMINOLEVULINIC ACID DEHYDRATASE; 1. |
| GO:0004655 porphobilinogen synthase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred porphobilinogen synthase (5-aminolevulinate dehydratase) activity, the core molecular function of ALAD across the ALAD/PBGS family. Reason: PAINT IBA (GO_REF:0000033) from PANTHER family PTHR11458. This is the defining molecular function of the family and of human ALAD, congruent with the experimental (EXP/IDA) annotations and the curated Rhea reaction in UniProt. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt Reaction=2 5-aminolevulinate = porphobilinogen + 2 H2O + H(+) file:human/ALAD/ALAD-uniprot.txt PANTHER; PTHR11458; DELTA-AMINOLEVULINIC ACID DEHYDRATASE; 1. Reactome:R-HSA-189439 catalyzes the asymmetric condensation of two molecules of ALA to form porphobilinogen |
| GO:0004655 porphobilinogen synthase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated electronic annotation (GO_REF:0000120; mappings from family signatures and the UniProt EC/Rhea catalytic-activity annotation) of the core porphobilinogen synthase activity. Reason: Correctly captures the core catalytic function; the curated UniProt catalytic-activity and function statements for this entry rest on experimental evidence on the human enzyme, and the family signatures (InterPro IPR001731 ALAD) place the protein in the porphobilinogen synthase family. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Reaction=2 5-aminolevulinate = porphobilinogen + 2 H2O + H(+) file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt InterPro; IPR001731; ALAD. |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location vocabulary mapping (GO_REF:0000044) to cytosol. Reason: Consistent with curated UniProt localization and Reactome; the enzyme acts in the cytosol. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0033014 tetrapyrrole biosynthetic process | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO electronic annotation (GO_REF:0000002, from the ALAD family signature) to the broad tetrapyrrole biosynthetic process. Reason: Correct but more general than the evidence supports for the human protein. Porphobilinogen is the common precursor of all tetrapyrroles, but humans make no chlorophyll or cobalamin, so in human cells the pathway ALAD feeds is heme biosynthesis. The specific descendant term heme biosynthetic process (GO:0006783), already carried by the gene by IBA/IDA/TAS, is the appropriate replacement. Proposed replacements: heme biosynthetic process Supporting Evidence: PMID:19812033 As PBGS catalyzes the first common step in the biosynthesis of the tetrapyrroles such as heme, low activity mutations in the human population are associated with the disease ALAD porphyria file:human/ALAD/ALAD-uniprot.txt PATHWAY: Porphyrin-containing compound metabolism; protoporphyrin-IX biosynthesis; coproporphyrinogen-III from 5-aminolevulinate: step 1/4. file:human/ALAD/ALAD-uniprot.txt InterPro; IPR001731; ALAD. |
| GO:0046872 metal ion binding | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO electronic annotation (GO_REF:0000002) for generic metal ion binding. ALAD is a zinc metalloenzyme (eight Zn2+ per octamer, four required for activity). Reason: Correct but general. The metal is identified experimentally as zinc, so the specific descendant zinc ion binding (GO:0008270), which the gene already carries by IDA, is the appropriate replacement. Inhibitory lead binding is captured separately by lead ion binding (GO:0032791). Proposed replacements: zinc ion binding Supporting Evidence: PMID:11032836 Human PBGS purifies with eight Zn(II) per homo-octamer; four ZnA have predominantly nonsulfur ligands, and four ZnB have predominantly sulfur ligands. Only four Zn(II) are required for activity. file:human/ALAD/ALAD-uniprot.txt Binds 8 zinc ions per octamer. Requires four zinc ions per octamer for full catalytic activity. |
| GO:0001666 response to hypoxia | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic (Ensembl Compara) projection from the rat ortholog of a broad stimulus-response profile. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to hypoxia. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005576 extracellular region | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara projection (GO_REF:0000107) of extracellular-region localization from the rat ortholog P06214. Reason: ALAD is a cytosolic enzyme with no secretion signal, and there is no evidence that it acts outside the cell. The projected extracellular localization, like the Reactome extracellular-region rows for this gene, rests on detection rather than on a secreted function; marked as over-annotated, consistently with the other extracellular-region rows. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0006783 heme biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated electronic annotation (GO_REF:0000120) to the core heme biosynthetic process. Reason: Correctly captures the core biological process; redundant with the IBA/IDA/TAS annotations. Supporting Evidence: PMID:3758678 A cDNA encoding human delta-aminolevulinic acid dehydratase (ALA-D; EC 4.2.1.24), the second enzyme in the heme biosynthetic pathway file:human/ALAD/ALAD-uniprot.txt PATHWAY: Porphyrin-containing compound metabolism; protoporphyrin-IX biosynthesis; coproporphyrinogen-III from 5-aminolevulinate: step 1/4. |
| GO:0006979 response to oxidative stress | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of a stress-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to oxidative stress. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0007584 response to nutrient | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of a nutrient-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to nutrient. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0009410 response to xenobiotic stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of a xenobiotic-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to xenobiotic stimulus. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0009635 response to herbicide | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of a herbicide-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to herbicide. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0009636 response to toxic substance | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of a toxic-substance-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to toxic substance. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0009725 response to hormone | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of a hormone-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to hormone. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0010038 response to metal ion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic projection of a metal-ion-response term from the rat ortholog. ALAD activity is strongly modulated by metals (Zn2+ cofactor; Pb2+ inhibition). Reason: Ensembl Compara projection (GO_REF:0000107) from rat P06214. Unlike most of the projected 'response to X' block, this one is biologically defensible for the gene itself: ALAD activity depends on bound zinc and is directly inhibited by divalent lead, which displaces the zinc cofactor. Kept as non-core toxicology-relevant biology. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Inhibited by divalent lead ions. The lead ions partially displace the zinc cofactor. file:human/ALAD/ALAD-uniprot.txt Binds 8 zinc ions per octamer. Requires four zinc ions per octamer for full catalytic activity. |
| GO:0010039 response to iron ion | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of an iron-ion-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to iron ions. Marked as over-annotated rather than removed, because the source observation may be real in rat. Iron is inserted at the last step of the pathway by ferrochelatase, not by ALAD. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0010043 response to zinc ion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic projection of a zinc-ion-response term from the rat ortholog. ALAD requires Zn2+ as its catalytic cofactor. Reason: Ensembl Compara projection (GO_REF:0000107) from rat P06214. Defensible in that ALAD activity depends on its catalytic zinc, so the enzyme's activity changes with zinc availability; kept as non-core rather than removed. Supporting Evidence: PMID:11032836 Human PBGS purifies with eight Zn(II) per homo-octamer; four ZnA have predominantly nonsulfur ligands, and four ZnB have predominantly sulfur ligands. Only four Zn(II) are required for activity. file:human/ALAD/ALAD-uniprot.txt Binds 8 zinc ions per octamer. Requires four zinc ions per octamer for full catalytic activity. |
| GO:0010044 response to aluminum ion | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of an aluminum-ion-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to aluminum ion. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0010212 response to ionizing radiation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of a radiation-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to ionizing radiation. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0010266 response to vitamin B1 | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of a vitamin B1-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to vitamin B1. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0010269 response to selenium ion | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of a selenium-ion-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to selenium ion. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0010288 response to lead ion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic projection of a lead-ion-response term from the rat ortholog. ALAD is the classic molecular target of lead poisoning. Reason: Biologically well supported: divalent lead inhibits ALAD by displacing the catalytic zinc, and ALAD is a principal target of lead. Retained as non-core toxicology-relevant biology. Supporting Evidence: PMID:11032836 Human porphobilinogen synthase (PBGS) is a main target in lead poisoning. file:human/ALAD/ALAD-uniprot.txt Inhibited by divalent lead ions. The lead ions partially displace the zinc cofactor. Reactome:R-HSA-190141 Lead binds to ALAD enzyme displacing half the zinc ions essential for its catalytic activity |
| GO:0014823 response to activity | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of a "response to activity" term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to activity. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0031667 response to nutrient levels | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of a nutrient-levels-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to nutrient levels. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0032025 response to cobalt ion | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of a cobalt-ion-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to cobalt ion. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0032496 response to lipopolysaccharide | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of an LPS-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to lipopolysaccharide. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0033197 response to vitamin E | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of a vitamin E-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to vitamin E. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0033273 response to vitamin | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of a vitamin-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to vitamin. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0043200 response to amino acid | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of an amino-acid-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to amino acid. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0045471 response to ethanol | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of an ethanol-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to ethanol. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0046685 response to arsenic-containing substance | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of an arsenic-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to arsenic-containing substance. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0046686 response to cadmium ion | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of a cadmium-ion-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to cadmium ion. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0046689 response to mercury ion | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of a mercury-ion-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to mercury ion. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0051384 response to glucocorticoid | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of a glucocorticoid-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to glucocorticoid. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0051597 response to methylmercury | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of a methylmercury-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to methylmercury. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0070541 response to platinum ion | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of a platinum-ion-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to platinum ion. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0070542 response to fatty acid | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic projection of a fatty-acid-response term from the rat ortholog. Reason: Ensembl Compara projection (GO_REF:0000107) from the rat ortholog P06214, one of a block of about thirty 'response to X' process terms. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure, which shows that ALAD is affected by the stimulus, not that it carries out a response process. ALAD is a constitutive cytosolic enzyme of heme synthesis, and nothing links its function specifically to fatty acid. Marked as over-annotated rather than removed, because the source observation may be real in rat. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0071284 cellular response to lead ion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic projection of a cellular-lead-response term from the rat ortholog. ALAD is directly inhibited by lead. Reason: Biologically defensible: lead directly targets and inhibits ALAD by displacing its catalytic zinc. Retained as non-core toxicology-relevant biology. Supporting Evidence: Reactome:R-HSA-190141 Lead is a major environmental toxin and this enzyme is one of its principal molecular targets file:human/ALAD/ALAD-uniprot.txt Inhibited by divalent lead ions. The lead ions partially displace the zinc cofactor. |
| GO:1904854 proteasome core complex binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic projection of a proteasome-core-complex-binding term from the rat ortholog, matching ALAD's characterized moonlighting role as the proteasome inhibitor CF-2. Reason: Corroborates the experimentally documented CF-2/proteasome-inhibitor moonlighting activity (PMID:8175643). This is a genuine secondary/moonlighting function, not the core catalytic role; kept as non-core. Supporting Evidence: PMID:8175643 The 240-kDa proteasome inhibitor has been reported to be an ATP-stabilized component (CF-2) of the 26 S proteasome complex. PMID:8175643 We now report that this inhibitory factor is indistinguishable from delta-aminolevulinic acid dehydratase (ALAD), the second enzyme in the pathway of heme synthesis |
| GO:0006785 heme B biosynthetic process | IDA PMID:11032836 The molecular mechanism of lead inhibition of human porphobi... | ACCEPT | Summary: Direct-assay involvement in heme B (protoheme) biosynthesis, the specific end-product of the pathway ALAD initiates at the pyrrole-forming step. Reason: A valid, more specific child of heme biosynthetic process. ALAD's condensation of ALA to porphobilinogen is an essential early step toward heme B. Consistent with the experimental characterization of human PBGS. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt PATHWAY: Porphyrin-containing compound metabolism; protoporphyrin-IX biosynthesis; coproporphyrinogen-III from 5-aminolevulinate: step 1/4. PMID:11032836 MinusZnA is fully active, whereas MinusZnB is far less active, verifying an important catalytic role for ZnB and the removed cysteine residues. |
| GO:0006783 heme biosynthetic process | TAS Reactome:R-HSA-189451 | ACCEPT | Summary: Traceable (Reactome) involvement in heme biosynthesis; ALAD catalyzes the cytosolic condensation of two ALA into porphobilinogen within the eight-enzyme heme pathway. Reason: Core biological process, supported by the curated Reactome heme-biosynthesis pathway. Supporting Evidence: Reactome:R-HSA-189451 Eight enzymes are involved in heme biosynthesis |
| GO:0032791 lead ion binding | EXP PMID:11032836 The molecular mechanism of lead inhibition of human porphobi... | KEEP AS NON CORE | Summary: Experimentally demonstrated lead binding. Pb2+ binds ALAD at a hybrid of the ZnA and ZnB metal sites, partially displacing the catalytic zinc and inhibiting activity. Reason: Well supported experimentally and mechanistically important for lead toxicology, but it represents inhibitory metal binding rather than the enzyme's core catalytic function; kept as non-core. Supporting Evidence: PMID:11032836 Comparison of Pb(II) inhibition of the mutants shows that ligands to both ZnA and ZnB interact with Pb(II). PMID:11032836 The data support a novel model where a high affinity lead site is a hybrid of the ZnA and ZnB sites. Reactome:R-HSA-190141 Lead binds to ALAD enzyme displacing half the zinc ions essential for its catalytic activity |
| GO:0004655 porphobilinogen synthase activity | EXP PMID:12897770 Control of tetrapyrrole biosynthesis by alternate quaternary... | ACCEPT | Summary: Experimental (crystallographic/biochemical) confirmation of human porphobilinogen synthase activity and its octamer/hexamer quaternary regulation. Reason: Directly supports the core molecular function with experimental evidence on the human enzyme. Supporting Evidence: PMID:12897770 Porphobilinogen synthase (PBGS) catalyzes the first common step in the biosynthesis of tetrapyrroles (such as heme and chlorophyll). PMID:12897770 Rearrangement of an N-terminal arm is responsible for this oligomeric switch, which results in profound changes in kinetic behavior. file:human/ALAD/ALAD-uniprot.txt Reaction=2 5-aminolevulinate = porphobilinogen + 2 H2O + H(+) |
| GO:0004655 porphobilinogen synthase activity | EXP PMID:19812033 Allosteric inhibition of human porphobilinogen synthase. | ACCEPT | Summary: Experimental confirmation of human porphobilinogen synthase activity as an allosterically regulated enzyme (octamer/hexamer/dimer equilibrium). Reason: Directly supports the core molecular function with experimental evidence on the human enzyme. Supporting Evidence: PMID:19812033 Human PBGS exists as an equilibrium of high activity octamers, low activity hexamers, and alternate dimer configurations PMID:19812033 Porphobilinogen synthase (PBGS) catalyzes the first common step in tetrapyrrole ( e.g. heme, chlorophyll) biosynthesis. file:human/ALAD/ALAD-uniprot.txt Reaction=2 5-aminolevulinate = porphobilinogen + 2 H2O + H(+) |
| GO:0005829 cytosol | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer (GO_REF:0000024) of cytosolic localization from the mouse ortholog. Reason: Consistent with the curated cytosolic location and the cytosolic phase of heme synthesis. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798748 | MARK AS OVER ANNOTATED | Summary: Reactome annotation placing ALAD in the extracellular region via neutrophil secretory-granule exocytosis. Reason: ALAD is a cytosolic enzyme with no secretion signal. Its placement in the extracellular region via the Reactome reaction 'Exocytosis of secretory granule lumen proteins' comes from neutrophil-granule cargo lists assembled from proteomic surveys, which routinely capture abundant cytosolic proteins, and there is no ALAD-specific evidence of granule packaging or regulated secretion. The location claim exceeds the evidence for this protein; marked as over-annotated, consistently across the extracellular-region and granule-lumen rows. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol Reactome:R-HSA-6798748 Secretory vesicles provide a reservoir of secreted proteins and membrane-associated receptors that are required at the earliest stages of the neutrophil-mediated inflammatory response. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6800434 | MARK AS OVER ANNOTATED | Summary: Reactome annotation placing ALAD in the extracellular region via ficolin-1-rich granule exocytosis. Reason: ALAD is a cytosolic enzyme with no secretion signal. Its placement in the extracellular region via the Reactome reaction 'Exocytosis of ficolin-rich granule lumen proteins' comes from neutrophil-granule cargo lists assembled from proteomic surveys, which routinely capture abundant cytosolic proteins, and there is no ALAD-specific evidence of granule packaging or regulated secretion. The location claim exceeds the evidence for this protein; marked as over-annotated, consistently across the extracellular-region and granule-lumen rows. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol Reactome:R-HSA-6800434 Ficoli-1 rich granules are a relatively new fourth neutrophil granule population that is enriched in the microbial lectin ficolin-1. |
| GO:0034774 secretory granule lumen | TAS Reactome:R-HSA-6798748 | MARK AS OVER ANNOTATED | Summary: Reactome annotation to the secretory granule lumen (neutrophil degranulation). Reason: ALAD is a cytosolic enzyme with no secretion signal. Its placement in the secretory granule lumen comes from neutrophil-granule cargo lists assembled from proteomic surveys, which routinely capture abundant cytosolic proteins, and there is no ALAD-specific evidence of granule packaging or regulated secretion. The location claim exceeds the evidence for this protein; marked as over-annotated, consistently across the extracellular-region and granule-lumen rows. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol Reactome:R-HSA-6798748 Secretory vesicles provide a reservoir of secreted proteins and membrane-associated receptors that are required at the earliest stages of the neutrophil-mediated inflammatory response. |
| GO:1904813 ficolin-1-rich granule lumen | TAS Reactome:R-HSA-6800434 | MARK AS OVER ANNOTATED | Summary: Reactome annotation to the ficolin-1-rich granule lumen (neutrophil degranulation). Reason: ALAD is a cytosolic enzyme with no secretion signal. Its placement in the ficolin-1-rich granule lumen comes from neutrophil-granule cargo lists assembled from proteomic surveys, which routinely capture abundant cytosolic proteins, and there is no ALAD-specific evidence of granule packaging or regulated secretion. The location claim exceeds the evidence for this protein; marked as over-annotated, consistently across the extracellular-region and granule-lumen rows. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol Reactome:R-HSA-6800434 Ficoli-1 rich granules are a relatively new fourth neutrophil granule population that is enriched in the microbial lectin ficolin-1. |
| GO:0004655 porphobilinogen synthase activity | IDA PMID:8175643 240-kDa proteasome inhibitor (CF-2) is identical to delta-am... | ACCEPT | Summary: Direct-assay porphobilinogen synthase (dehydratase) activity; the CF-2/proteasome-inhibitor protein retained ALA-dehydratase activity, confirming its identity as ALAD. Reason: Supports the core catalytic function; the study showed similar dehydratase specific activities in CF-2 and ALAD and dehydratase activity in recombinant ALAD. Supporting Evidence: PMID:8175643 5) similar dehydratase and proteasome inhibitor specific activities in both proteins; and 6) the presence of both activities in recombinant ALAD. PMID:8175643 We now report that this inhibitory factor is indistinguishable from delta-aminolevulinic acid dehydratase (ALAD), the second enzyme in the pathway of heme synthesis |
| GO:1901799 negative regulation of proteasomal protein catabolic process | IDA PMID:8175643 240-kDa proteasome inhibitor (CF-2) is identical to delta-am... | KEEP AS NON CORE | Summary: Direct-assay evidence that ALAD (as CF-2) inhibits the proteasome, a moonlighting function distinct from its heme-synthesis role. Reason: Genuine gene-sharing/moonlighting activity: the 240-kDa proteasome inhibitor CF-2 is identical to ALAD and inhibits the ATP/ubiquitin-dependent proteasome pathway. Not the core catalytic function; retained as non-core. Supporting Evidence: PMID:8175643 The 240-kDa proteasome inhibitor has been reported to be an ATP-stabilized component (CF-2) of the 26 S proteasome complex. PMID:8175643 5) similar dehydratase and proteasome inhibitor specific activities in both proteins; and 6) the presence of both activities in recombinant ALAD. PMID:8175643 The dual role of this protein as CF-2 in the ATP/ubiquitin-dependent pathway and in heme synthesis may be an example of |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: High-throughput proteomic detection of ALAD in urinary/prostatic exosome preparations. Reason: Direct detection in a high-throughput exosome proteome. Exosomes enclose cytoplasm, so an abundant cytosolic enzyme can genuinely be present in them; the observation is accepted as a location, but it is peripheral and indicates no extracellular function. Supporting Evidence: PMID:23533145 exosome preparations were characterized by a shotgun proteomics procedure |
| GO:0005634 nucleus | HDA PMID:21630459 Proteomic characterization of the human sperm nucleus. | KEEP AS NON CORE | Summary: High-throughput proteomic detection of ALAD in isolated human sperm nuclei. Reason: Direct detection in a high-throughput sperm-nucleus proteome. There is no functional evidence for a nuclear role of ALAD, and the curated location is cytosolic; kept as a peripheral, non-core observed location. Supporting Evidence: PMID:21630459 403 different proteins have been identified from the isolated sperm nuclei |
| GO:0005829 cytosol | TAS Reactome:R-HSA-189439 | ACCEPT | Summary: Reactome traceable annotation placing the ALAD-catalyzed ALA-condensation reaction in the cytosol. Reason: Core localization; the enzyme acts in the cytosol. Supporting Evidence: Reactome:R-HSA-189451 The next four steps take place in the cytosol. file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-190141 | ACCEPT | Summary: Reactome traceable annotation of cytosolic localization (ALAD-Pb2+ binding reaction). Reason: Core localization; consistent with UniProt and the other cytosol annotations. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol Reactome:R-HSA-189451 The next four steps take place in the cytosol. |
| GO:0004655 porphobilinogen synthase activity | IDA PMID:11032836 The molecular mechanism of lead inhibition of human porphobi... | ACCEPT | Summary: Direct-assay porphobilinogen synthase activity of purified/recombinant human PBGS, with kinetic characterization and cysteine mutagenesis defining the catalytic zinc site. Reason: Strong experimental support for the core molecular function on the human enzyme. Supporting Evidence: PMID:11032836 MinusZnA is fully active, whereas MinusZnB is far less active, verifying an important catalytic role for ZnB and the removed cysteine residues. file:human/ALAD/ALAD-uniprot.txt Reaction=2 5-aminolevulinate = porphobilinogen + 2 H2O + H(+) file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. |
| GO:0006783 heme biosynthetic process | IDA PMID:11032836 The molecular mechanism of lead inhibition of human porphobi... | ACCEPT | Summary: Direct-assay involvement in heme biosynthesis via characterization of human PBGS as the pyrrole-forming enzyme of the heme pathway. Reason: Core biological process, experimentally supported on the human enzyme. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen. file:human/ALAD/ALAD-uniprot.txt PATHWAY: Porphyrin-containing compound metabolism; protoporphyrin-IX biosynthesis; coproporphyrinogen-III from 5-aminolevulinate: step 1/4. |
| GO:0008270 zinc ion binding | IDA PMID:11032836 The molecular mechanism of lead inhibition of human porphobi... | ACCEPT | Summary: Direct-assay zinc binding: human PBGS purifies with eight Zn2+ per homo-octamer, four of which are required for activity; cysteine mutagenesis maps the catalytic ZnB site. Reason: Direct evidence on the human enzyme: purified PBGS carries eight Zn(II) per octamer, and removing the cysteine ligands of the ZnB site largely abolishes activity. Zinc is the catalytic metal of the porphobilinogen synthase reaction and the site attacked by lead, so zinc binding is part of the core catalytic function (also listed in core_functions). Supporting Evidence: PMID:11032836 Human PBGS purifies with eight Zn(II) per homo-octamer; four ZnA have predominantly nonsulfur ligands, and four ZnB have predominantly sulfur ligands. Only four Zn(II) are required for activity. PMID:11032836 MinusZnA is fully active, whereas MinusZnB is far less active, verifying an important catalytic role for ZnB and the removed cysteine residues. file:human/ALAD/ALAD-uniprot.txt Binds 8 zinc ions per octamer. Requires four zinc ions per octamer for full catalytic activity. |
| GO:0042802 identical protein binding | IPI PMID:11032836 The molecular mechanism of lead inhibition of human porphobi... | KEEP AS NON CORE | Summary: Self-interaction (ALAD binds ALAD), reflecting its assembly into a homo-octamer/homohexamer. Reason: The self-interaction is real: human ALAD assembles into a homo-octamer (active) or homo-hexamer (low activity), and the quaternary equilibrium governs activity and porphyria. identical protein binding is not GO:0005515 and is as specific as an MF term for this self-association allows; the biologically meaningful consequence is captured by protein homooligomerization. Kept as non-core. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt SUBUNIT: Homooctamer; active form. Homohexamer; low activity form. PMID:11032836 Human PBGS purifies with eight Zn(II) per homo-octamer; four ZnA have predominantly nonsulfur ligands, and four ZnB have predominantly sulfur ligands. Only four Zn(II) are required for activity. |
| GO:0051260 protein homooligomerization | IPI PMID:11032836 The molecular mechanism of lead inhibition of human porphobi... | KEEP AS NON CORE | Summary: Homo-oligomerization into the catalytically active octamer (and low-activity hexamer), central to ALAD's morpheein-type allosteric regulation. Reason: Functionally meaningful: the octamer is the active oligomeric form and the octamer/hexamer equilibrium governs activity and disease. Retained as non-core biology that supports, but is not itself, the catalytic function. Supporting Evidence: file:human/ALAD/ALAD-uniprot.txt SUBUNIT: Homooctamer; active form. Homohexamer; low activity form. PMID:19812033 Human PBGS exists as an equilibrium of high activity octamers, low activity hexamers, and alternate dimer configurations |
| GO:0003824 catalytic activity | TAS PMID:2063868 delta-Aminolevulinate dehydratase deficient porphyria: ident... | MODIFY | Summary: Traceable annotation to generic catalytic activity; ALAD's specific catalytic function is porphobilinogen synthase activity. Reason: The root-level "catalytic activity" term is uninformative for a well-characterized enzyme. It should be replaced by the specific molecular function porphobilinogen synthase activity (GO:0004655). Proposed replacements: porphobilinogen synthase activity Supporting Evidence: PMID:2063868 results from the markedly deficient activity of the heme biosynthetic enzyme, delta-aminolevulinate dehydratase (ALA-D) file:human/ALAD/ALAD-uniprot.txt Reaction=2 5-aminolevulinate = porphobilinogen + 2 H2O + H(+) |
| GO:0004655 porphobilinogen synthase activity | TAS PMID:3463993 Human delta-aminolevulinate dehydratase: nucleotide sequence... | ACCEPT | Summary: Traceable annotation of porphobilinogen synthase activity from the cDNA-cloning paper that identified ALA-D (PBGS, EC 4.2.1.24). Reason: Supports the core molecular function; consistent with all other MF evidence. Supporting Evidence: PMID:3463993 Two cDNAs encoding human delta-aminolevulinate dehydratase (ALA-D; porphobilinogen synthase; EC 4.2.1.24), the second enzyme in the heme biosynthetic pathway |
| GO:0006783 heme biosynthetic process | TAS PMID:3758678 Molecular cloning of a cDNA for human delta-aminolevulinate ... | ACCEPT | Summary: Traceable annotation of involvement in heme biosynthesis from the cDNA-cloning paper that identified ALA-D as the second enzyme of the heme pathway. Reason: Supports the core biological process. Supporting Evidence: PMID:3758678 A cDNA encoding human delta-aminolevulinic acid dehydratase (ALA-D; EC 4.2.1.24), the second enzyme in the heme biosynthetic pathway |
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Download this section (compressed HTML)Q: Beyond the well-characterized CF-2/proteasome-inhibitor moonlighting activity, is there a physiological context (e.g. specific tissues or stress states) in which ALAD's proteasome regulation is functionally significant in vivo?
Q: Do the ALAD*1/ALAD*2 (K59N) allele differences alter any function beyond susceptibility to lead accumulation?
Experiment: Quantitative structure-function analysis of the octamer/hexamer equilibrium for each ALAD-deficiency porphyria variant, correlating hexamer propensity with residual PBGS activity and clinical severity.
Type: biophysical/enzyme kinetics
Experiment: Interactome and proximity-labeling studies in erythroid and hepatic cells to test whether the CF-2/proteasome-inhibitory role is physiologically engaged or is an in vitro property of an abundant enzyme.
Type: proximity labeling / interactome
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