UROS

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004852 uroporphyrinogen-III synthase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically-inferred core catalytic activity. This is the defining molecular function of UROS, well supported by direct experimental evidence in human and orthologs. Reason: PAINT IBA (GO_REF:0000033) within PANTHER family PTHR12390 (uroporphyrinogen III synthase). The defining activity of the family and of human UROS, concordant with the IDA/EXP evidence on the purified and recombinant human enzyme. Supporting Evidence: PMID:3174619 is responsible for conversion of the linear tetrapyrrole, hydroxymethylbilane, to the cyclic tetrapyrrole, uroporphyrinogen III. file:human/UROS/UROS-uniprot.txt Reaction=hydroxymethylbilane = uroporphyrinogen III + H2O file:human/UROS/UROS-uniprot.txt PANTHER; PTHR12390; UROPORPHYRINOGEN III SYNTHASE; 1.
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: UROS acts in the cytosol, consistent with it being one of the four cytosolic enzymes of heme biosynthesis. Reason: PAINT IBA (GO_REF:0000033) from PTHR12390; concordant with the UniProt location and with the cytosolic phase of heme synthesis. Supporting Evidence: file:human/UROS/UROS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol PMID:18004775 an efficient expression and purification procedure was developed for these cytosolic enzymes of heme biosynthesis file:human/UROS/UROS-uniprot.txt PANTHER; PTHR12390; UROPORPHYRINOGEN III SYNTHASE; 1.
GO:0006780 uroporphyrinogen III biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: UROS produces uroporphyrinogen III, so this is the immediate biosynthetic process it drives. Reason: PAINT IBA (GO_REF:0000033) from PTHR12390. UROS makes uroporphyrinogen III itself, so this is the immediate process of its catalytic step. Supporting Evidence: PMID:3174619 is responsible for conversion of the linear tetrapyrrole, hydroxymethylbilane, to the cyclic tetrapyrrole, uroporphyrinogen III. PMID:11689424 Uroporphyrinogen III synthase, U3S, the fourth enzyme in the porphyrin biosynthetic pathway, catalyzes cyclization of the linear tetrapyrrole, hydroxymethylbilane, to the macrocyclic uroporphyrino gen III file:human/UROS/UROS-uniprot.txt PANTHER; PTHR12390; UROPORPHYRINOGEN III SYNTHASE; 1.
GO:0004852 uroporphyrinogen-III synthase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assertion of the core catalytic activity (ARBA/RHEA/EC/InterPro), matching EC 4.2.1.75 and RHEA:18965. Reason: Correct and consistent with the experimentally verified molecular function. Supporting Evidence: file:human/UROS/UROS-uniprot.txt Reaction=hydroxymethylbilane = uroporphyrinogen III + H2O file:human/UROS/UROS-uniprot.txt Catalyzes cyclization of the linear tetrapyrrole, hydroxymethylbilane, to the macrocyclic uroporphyrinogen III, the branch point for the various sub-pathways leading to the wide diversity of porphyrins file:human/UROS/UROS-uniprot.txt InterPro; IPR003754; 4pyrrol_synth_uPrphyn_synth.
GO:0005829 cytosol	IEA GO_REF:0000044	ACCEPT	Summary: Electronic location annotation from UniProt subcellular-location mapping; matches the curated cytosolic localization. Reason: Correct location, concordant with UniProt SUBCELLULAR LOCATION. Supporting Evidence: file:human/UROS/UROS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0006785 heme B biosynthetic process	IEA GO_REF:0000117	ACCEPT	Summary: ARBA electronic annotation (GO_REF:0000117) to heme B biosynthetic process. Reason: Correct and specific for the human enzyme. Uroporphyrinogen III is a branch point in organisms that also make siroheme, chlorophyll or cobalamin, but humans make none of these, so in human cells UROS output goes to heme; heme B (protoheme) is the pathway's end product, and the process term covers every step of its formation. The same convention is applied to the other heme-pathway enzymes in this review set. The ARBA rule itself is not evidence; the claim rests on the curated function and pathway. Supporting Evidence: PMID:3805019 Uroporphyrinogen III synthase (hydroxymethylbilane hydro-lyase (cyclizing); EC 4.2.1.75), the fourth enzyme in the heme biosynthetic pathway, was purified to homogeneity from human erythrocytes. file:human/UROS/UROS-uniprot.txt PATHWAY: Porphyrin-containing compound metabolism; protoporphyrin-IX biosynthesis; coproporphyrinogen-III from 5-aminolevulinate: step 3/4.
GO:0033014 tetrapyrrole biosynthetic process	IEA GO_REF:0000002	MODIFY	Summary: InterPro2GO electronic annotation (GO_REF:0000002) to tetrapyrrole biosynthetic process. Reason: Correct but general. The specific process for this enzyme is uroporphyrinogen III biosynthetic process (GO:0006780), a descendant term that the gene already carries by IBA and IDA; that is the appropriate replacement. Proposed replacements: uroporphyrinogen III biosynthetic process Supporting Evidence: PMID:3174619 is responsible for conversion of the linear tetrapyrrole, hydroxymethylbilane, to the cyclic tetrapyrrole, uroporphyrinogen III. file:human/UROS/UROS-uniprot.txt InterPro; IPR003754; 4pyrrol_synth_uPrphyn_synth.
GO:0005542 folic acid binding	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Folic acid binding (IEA), transferred from rat Uros, where it derives from a 1984 direct assay (PMID:6466301); later work on the enzyme does not support a folate cofactor. Reason: The row is transferred from rat Uros, annotated by direct assay in a 1984 study (PMID:6466301), so an experimental observation of folate associated with the purified enzyme lies behind it. A folate cofactor has not been borne out by later structural and mechanistic work on uroporphyrinogen-III synthase, whose reaction needs no cofactor. The activity is an unconfirmed historical observation rather than a refuted one, and the row is marked as an over-annotation rather than removed. Supporting Evidence: PMID:3805019 Using hydroxymethylbilane as substrate, the purified enzyme formed uroporphyrinogen III in the absence of hydroxymethylbilane synthase or other cofactors. file:human/UROS/UROS-uniprot.txt Catalyzes cyclization of the linear tetrapyrrole, hydroxymethylbilane, to the macrocyclic uroporphyrinogen III, the branch point for the various sub-pathways leading to the wide diversity of porphyrins
GO:0006780 uroporphyrinogen III biosynthetic process	IEA GO_REF:0000107	ACCEPT	Summary: Electronic transfer of the immediate biosynthetic process from the rat ortholog; correct. Reason: Matches the enzyme's direct product; concordant with human experimental annotations to the same term. Supporting Evidence: PMID:3174619 is responsible for conversion of the linear tetrapyrrole, hydroxymethylbilane, to the cyclic tetrapyrrole, uroporphyrinogen III. PMID:3805019 Using hydroxymethylbilane as substrate, the purified enzyme formed uroporphyrinogen III in the absence of hydroxymethylbilane synthase or other cofactors.
GO:0070541 response to platinum ion	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Generic stress/perturbation-response term electronically transferred from the rat ortholog (Q5XIF2). This is not part of the characterized core molecular role of this heme-biosynthesis enzyme. Reason: Ensembl Compara projection (GO_REF:0000107) from rat. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure; no effect of platinum ions on UROS was found in the literature read for this review, and UROS is a constitutive cytosolic enzyme of heme synthesis. The projected process claim exceeds the evidence; marked as over-annotated rather than removed, because the rat observation may be real. Supporting Evidence: file:human/UROS/UROS-uniprot.txt Catalyzes cyclization of the linear tetrapyrrole, hydroxymethylbilane, to the macrocyclic uroporphyrinogen III, the branch point for the various sub-pathways leading to the wide diversity of porphyrins file:human/UROS/UROS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0071243 cellular response to arsenic-containing substance	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Generic response term electronically transferred from the rat ortholog; not a characterized function of human UROS. Reason: Ensembl Compara projection (GO_REF:0000107) from rat. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure; no effect of arsenic-containing substances on UROS was found in the literature read for this review, and UROS is a constitutive cytosolic enzyme of heme synthesis. The projected process claim exceeds the evidence; marked as over-annotated rather than removed, because the rat observation may be real. Supporting Evidence: file:human/UROS/UROS-uniprot.txt Catalyzes cyclization of the linear tetrapyrrole, hydroxymethylbilane, to the macrocyclic uroporphyrinogen III, the branch point for the various sub-pathways leading to the wide diversity of porphyrins file:human/UROS/UROS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0071418 cellular response to amine stimulus	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Generic response term electronically transferred from the rat ortholog; not a characterized function of human UROS. Reason: Ensembl Compara projection (GO_REF:0000107) from rat. Rat 'response to' annotations of this kind generally record that the ortholog's expression or activity changed after an exposure; no effect of amines on UROS was found in the literature read for this review, and UROS is a constitutive cytosolic enzyme of heme synthesis. The projected process claim exceeds the evidence; marked as over-annotated rather than removed, because the rat observation may be real. Supporting Evidence: file:human/UROS/UROS-uniprot.txt Catalyzes cyclization of the linear tetrapyrrole, hydroxymethylbilane, to the macrocyclic uroporphyrinogen III, the branch point for the various sub-pathways leading to the wide diversity of porphyrins file:human/UROS/UROS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0006785 heme B biosynthetic process	IDA PMID:18004775 Human uroporphyrinogen III synthase: NMR-based mapping of th...	ACCEPT	Summary: Experimental annotation placing UROS in heme biosynthesis. However heme b is a distal, specific product; UROS acts at the uroporphyrinogen III branch point upstream of the heme-specific sub-pathway and its product feeds all porphyrins, not specifically heme b. Reason: Correct and specific for the human enzyme. Uroporphyrinogen III is a branch point in organisms that also make siroheme, chlorophyll or cobalamin, but humans make none of these, so in human cells UROS output goes to heme; heme B (protoheme) is the pathway's end product, and the process term covers every step of its formation. The same convention is applied to the other heme-pathway enzymes in this review set. Experimental annotation on the purified human cytosolic enzymes; deferring to the curator. Supporting Evidence: PMID:18004775 Uroporphyrinogen III synthase (URO-synthase) catalyzes the cyclization and D-ring isomerization of hydroxymethylbilane (HMB) to uroporphyrinogen (URO'gen) III, the cyclic tetrapyrrole and physiologic precursor of heme, chlorophyl, and corrin. PMID:18004775 an efficient expression and purification procedure was developed for these cytosolic enzymes of heme biosynthesis
GO:0006783 heme biosynthetic process	TAS Reactome:R-HSA-189451	ACCEPT	Summary: UROS is one of the eight enzymes of heme biosynthesis (the fourth step, one of the four cytosolic steps), producing the uroporphyrinogen III precursor. Reason: Core biological process for this enzyme; well supported by literature and the Reactome heme biosynthesis pathway. Supporting Evidence: Reactome:R-HSA-189451 The next two steps convert four molecules of PBG into the cyclic tetrapyrrole uroporphyringen III, which is then decarboxylated into coproporphyrinogen III. PMID:3805019 Uroporphyrinogen III synthase (hydroxymethylbilane hydro-lyase (cyclizing); EC 4.2.1.75), the fourth enzyme in the heme biosynthetic pathway, was purified to homogeneity from human erythrocytes.
GO:0004852 uroporphyrinogen-III synthase activity	TAS Reactome:R-HSA-189488	ACCEPT	Summary: Reactome-curated statement of the core catalytic activity (HMB to uroporphyrinogen III). Reason: Correct core molecular function, concordant with experimental evidence. Supporting Evidence: Reactome:R-HSA-189488 Cytosolic uroporphyrinogen III synthase (URO3S) catalyzes the conversion file:human/UROS/UROS-uniprot.txt Reaction=hydroxymethylbilane = uroporphyrinogen III + H2O
GO:0004852 uroporphyrinogen-III synthase activity	EXP PMID:11689424 Crystal structure of human uroporphyrinogen III synthase.	ACCEPT	Summary: Experimental (crystal structure with catalytic activity/mutagenesis) confirmation of the uroporphyrinogen-III synthase activity, including the ring closure with D-ring flipping. Reason: Direct experimental support for the defining molecular function. Supporting Evidence: PMID:11689424 Uroporphyrinogen III synthase, U3S, the fourth enzyme in the porphyrin biosynthetic pathway, catalyzes cyclization of the linear tetrapyrrole, hydroxymethylbilane, to the macrocyclic uroporphyrino gen III file:human/UROS/UROS-uniprot.txt Reaction=hydroxymethylbilane = uroporphyrinogen III + H2O
GO:0005829 cytosol	ISS GO_REF:0000024	ACCEPT	Summary: Cytosolic localization inferred by sequence similarity to the mouse ortholog; consistent with the curated human localization. Reason: Correct location; concordant with UniProt and Reactome. Supporting Evidence: file:human/UROS/UROS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol PMID:18004775 an efficient expression and purification procedure was developed for these cytosolic enzymes of heme biosynthesis
GO:0005829 cytosol	TAS Reactome:R-HSA-189488	ACCEPT	Summary: Reactome places the UROS reaction in the cytosol. Reason: Correct location, consistent with the four cytosolic steps of heme biosynthesis. Supporting Evidence: Reactome:R-HSA-189488 Cytosolic uroporphyrinogen III synthase (URO3S) catalyzes the conversion file:human/UROS/UROS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0006783 heme biosynthetic process	IC PMID:18004775 Human uroporphyrinogen III synthase: NMR-based mapping of th...	ACCEPT	Summary: Curator inference (from the GO:0004852 molecular function) that UROS participates in heme biosynthesis. Reason: Sound inference; UROS is the fourth enzyme of the heme biosynthetic pathway and this is a core biological process. Supporting Evidence: PMID:18004775 an efficient expression and purification procedure was developed for these cytosolic enzymes of heme biosynthesis PMID:18004775 Uroporphyrinogen III synthase (URO-synthase) catalyzes the cyclization and D-ring isomerization of hydroxymethylbilane (HMB) to uroporphyrinogen (URO'gen) III, the cyclic tetrapyrrole and physiologic precursor of heme, chlorophyl, and corrin.
GO:0004852 uroporphyrinogen-III synthase activity	IDA PMID:3805019 Purification and properties of uroporphyrinogen III synthase...	ACCEPT	Summary: The enzyme was purified to homogeneity from human erythrocytes and shown to form uroporphyrinogen III from hydroxymethylbilane, directly demonstrating uroporphyrinogen-III synthase activity. Reason: Direct experimental demonstration of the core catalytic activity. Supporting Evidence: PMID:3805019 Using hydroxymethylbilane as substrate, the purified enzyme formed uroporphyrinogen III in the absence of hydroxymethylbilane synthase or other cofactors. PMID:3805019 Uroporphyrinogen III synthase (hydroxymethylbilane hydro-lyase (cyclizing); EC 4.2.1.75), the fourth enzyme in the heme biosynthetic pathway, was purified to homogeneity from human erythrocytes.
GO:0005739 mitochondrion	ISS GO_REF:0000024	REMOVE	Summary: Mitochondrial localization asserted by an old (2009) sequence-similarity inference from UniProtKB:P51163. UROS is a cytosolic enzyme, one of the four cytosolic steps of heme biosynthesis; UniProt and Reactome both localize it to the cytosol only. Reason: Root-organelle ISS row (GO_REF:0000024) transferred from mouse P51163, checked per the organelle policy. The organelle claim does not hold for UROS: it is a soluble monomeric enzyme of the cytosolic phase of heme synthesis with no mitochondrial targeting sequence, the human enzyme was purified from mature erythrocytes, which lack mitochondria, and the curated and pathway locations are cytosolic. The sequence-similarity transfer over-propagates a location that the target's own evidence contradicts; removed. Supporting Evidence: file:human/UROS/UROS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol PMID:18004775 an efficient expression and purification procedure was developed for these cytosolic enzymes of heme biosynthesis PMID:3805019 Uroporphyrinogen III synthase (hydroxymethylbilane hydro-lyase (cyclizing); EC 4.2.1.75), the fourth enzyme in the heme biosynthetic pathway, was purified to homogeneity from human erythrocytes.
GO:0005829 cytosol	NAS PMID:3805019 Purification and properties of uroporphyrinogen III synthase...	ACCEPT	Summary: Non-traceable author statement of cytosolic localization; the enzyme was purified from human erythrocyte cytosol. Reason: Consistent with the well-established cytosolic localization of UROS. Supporting Evidence: file:human/UROS/UROS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol PMID:3805019 Uroporphyrinogen III synthase (hydroxymethylbilane hydro-lyase (cyclizing); EC 4.2.1.75), the fourth enzyme in the heme biosynthetic pathway, was purified to homogeneity from human erythrocytes.
GO:0006780 uroporphyrinogen III biosynthetic process	IDA PMID:3805019 Purification and properties of uroporphyrinogen III synthase...	ACCEPT	Summary: The purified enzyme formed uroporphyrinogen III from hydroxymethylbilane, directly demonstrating its role in uroporphyrinogen III biosynthesis. Reason: Direct experimental support for the immediate biosynthetic process. Supporting Evidence: PMID:3805019 Using hydroxymethylbilane as substrate, the purified enzyme formed uroporphyrinogen III in the absence of hydroxymethylbilane synthase or other cofactors.
GO:0006783 heme biosynthetic process	IDA PMID:3805019 Purification and properties of uroporphyrinogen III synthase...	ACCEPT	Summary: The paper characterizes UROS as the fourth enzyme in the heme biosynthetic pathway, purified from human erythrocytes. Reason: Core biological process; UROS is an essential heme-biosynthesis enzyme. Supporting Evidence: PMID:3805019 Uroporphyrinogen III synthase (hydroxymethylbilane hydro-lyase (cyclizing); EC 4.2.1.75), the fourth enzyme in the heme biosynthetic pathway, was purified to homogeneity from human erythrocytes.
GO:0004852 uroporphyrinogen-III synthase activity	IDA PMID:18004775 Human uroporphyrinogen III synthase: NMR-based mapping of th...	ACCEPT	Summary: NMR active-site mapping study of URO-synthase confirming the enzyme catalyzes cyclization and D-ring isomerization of hydroxymethylbilane to uroporphyrinogen III. Reason: Direct experimental support for the core catalytic activity. Supporting Evidence: PMID:18004775 Uroporphyrinogen III synthase (URO-synthase) catalyzes the cyclization and D-ring isomerization of hydroxymethylbilane (HMB) to uroporphyrinogen (URO'gen) III, the cyclic tetrapyrrole and physiologic precursor of heme, chlorophyl, and corrin. file:human/UROS/UROS-uniprot.txt Reaction=hydroxymethylbilane = uroporphyrinogen III + H2O
GO:0006780 uroporphyrinogen III biosynthetic process	IDA PMID:18004775 Human uroporphyrinogen III synthase: NMR-based mapping of th...	ACCEPT	Summary: The enzyme catalyzes the formation of uroporphyrinogen III from hydroxymethylbilane, directly implicating it in uroporphyrinogen III biosynthesis. Reason: Direct experimental support for the immediate biosynthetic process. Supporting Evidence: PMID:18004775 Uroporphyrinogen III synthase (URO-synthase) catalyzes the cyclization and D-ring isomerization of hydroxymethylbilane (HMB) to uroporphyrinogen (URO'gen) III, the cyclic tetrapyrrole and physiologic precursor of heme, chlorophyl, and corrin.
GO:0004852 uroporphyrinogen-III synthase activity	IDA PMID:3174619 Human uroporphyrinogen III synthase: molecular cloning, nucl...	ACCEPT	Summary: Molecular cloning and expression of the full-length human URO-synthase cDNA in E. coli yielded high levels of enzymatic activity, confirming the gene product's uroporphyrinogen-III synthase activity. Reason: Direct experimental support (functional expression) for the core catalytic activity. Supporting Evidence: PMID:3174619 is responsible for conversion of the linear tetrapyrrole, hydroxymethylbilane, to the cyclic tetrapyrrole, uroporphyrinogen III.
GO:0006780 uroporphyrinogen III biosynthetic process	IDA PMID:3174619 Human uroporphyrinogen III synthase: molecular cloning, nucl...	ACCEPT	Summary: The cloned/expressed enzyme is responsible for conversion of hydroxymethylbilane to uroporphyrinogen III. Reason: Direct experimental support for the immediate biosynthetic process. Supporting Evidence: PMID:3174619 is responsible for conversion of the linear tetrapyrrole, hydroxymethylbilane, to the cyclic tetrapyrrole, uroporphyrinogen III.

Gene Description

Existing Annotations Review

Core Functions

Uroporphyrinogen-III synthase activity - catalyzes the cyclization of the linear tetrapyrrole hydroxymethylbilane into uroporphyrinogen III, with inversion of ring D, ensuring formation of the physiological III isomer.

References

📚 Additional Documentation

Notes

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