id: P10746
gene_symbol: UROS
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Uroporphyrinogen-III synthase (URO-synthase, EC 4.2.1.75), the fourth
  enzyme of the heme biosynthetic pathway. It catalyzes the cyclization of the linear
  tetrapyrrole hydroxymethylbilane into the macrocyclic uroporphyrinogen III, with
  concurrent inversion (flipping) of ring D, thereby generating the physiological
  III isomer; in its absence hydroxymethylbilane spontaneously and non-enzymatically
  cyclizes to the useless uroporphyrinogen I isomer. Uroporphyrinogen III is the
  branch point precursor for all biological porphyrins (heme, chlorophyll, corrins
  including vitamin B12, siroheme, and F430). The enzyme is a monomer acting in the
  cytosol, as one of the four cytosolic steps of heme biosynthesis. In humans, loss
  of UROS activity causes the autosomal recessive disorder congenital erythropoietic
  porphyria (CEP, Gunther disease), characterized by accumulation of the uroporphyrin
  I isomer and severe cutaneous photosensitivity.
existing_annotations:
- term:
    id: GO:0004852
    label: uroporphyrinogen-III synthase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetically-inferred core catalytic activity. This is the defining
      molecular function of UROS, well supported by direct experimental evidence in
      human and orthologs.
    action: ACCEPT
    reason: Correct molecular function at the appropriate level of specificity; the
      IBA is concordant with human IDA/EXP evidence for the same term.
    supported_by:
    - reference_id: PMID:3174619
      supporting_text: the cyclic tetrapyrrole, uroporphyrinogen III
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: UROS acts in the cytosol, consistent with it being one of the four cytosolic
      enzymes of heme biosynthesis.
    action: ACCEPT
    reason: Correct subcellular location; concordant with UniProt subcellular location
      (Cytoplasm, cytosol) and Reactome.
    supported_by:
    - reference_id: PMID:18004775
      supporting_text: cytosolic enzymes of heme biosynthesis
- term:
    id: GO:0006780
    label: uroporphyrinogen III biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: UROS produces uroporphyrinogen III, so this is the immediate biosynthetic
      process it drives.
    action: ACCEPT
    reason: Directly reflects the enzyme's product; well supported experimentally.
    supported_by:
    - reference_id: PMID:3174619
      supporting_text: the cyclic tetrapyrrole, uroporphyrinogen III
- term:
    id: GO:0004852
    label: uroporphyrinogen-III synthase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic assertion of the core catalytic activity (ARBA/RHEA/EC/InterPro),
      matching EC 4.2.1.75 and RHEA:18965.
    action: ACCEPT
    reason: Correct and consistent with the experimentally verified molecular function.
    supported_by:
    - reference_id: file:human/UROS/UROS-uniprot.txt
      supporting_text: Catalyzes cyclization of the linear tetrapyrrole,
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic location annotation from UniProt subcellular-location mapping;
      matches the curated cytosolic localization.
    action: ACCEPT
    reason: Correct location, concordant with UniProt SUBCELLULAR LOCATION.
    supported_by:
    - reference_id: file:human/UROS/UROS-uniprot.txt
      supporting_text: Cytoplasm, cytosol
- term:
    id: GO:0006785
    label: heme B biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: UROS produces uroporphyrinogen III, the branch-point precursor for ALL
      porphyrins (heme, chlorophyll, corrins/B12, siroheme, F430), not specifically
      heme b. Heme b is a distal, specific product several enzymatic steps downstream.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-specific for an enzyme acting at the branch point upstream of the
      heme-specific sub-pathway; the general heme biosynthetic process (GO:0006783)
      and tetrapyrrole biosynthetic process (GO:0033014) capture its role more
      appropriately.
    supported_by:
    - reference_id: PMID:11689424
      supporting_text: the fourth enzyme in the porphyrin biosynthetic pathway
- term:
    id: GO:0033014
    label: tetrapyrrole biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: UROS synthesizes the cyclic tetrapyrrole uroporphyrinogen III, so this
      broader biosynthetic-process term is correct.
    action: ACCEPT
    reason: Accurate parent process; uroporphyrinogen III is a tetrapyrrole and the
      precursor of all downstream tetrapyrroles.
    supported_by:
    - reference_id: PMID:3174619
      supporting_text: the cyclic tetrapyrrole, uroporphyrinogen III
- term:
    id: GO:0005542
    label: folic acid binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Electronic transfer from the rat ortholog (Q5XIF2) via Ensembl Compara.
      UROS is a hydroxymethylbilane cyclizing lyase; its substrate is a linear
      tetrapyrrole, not a pterin/folate, and there is no biochemical evidence that
      UROS binds folic acid.
    action: REMOVE
    reason: Spurious electronically-transferred function unsupported by any evidence
      for UROS; incompatible with its characterized substrate and mechanism.
    supported_by:
    - reference_id: file:human/UROS/UROS-uniprot.txt
      supporting_text: Catalyzes cyclization of the linear tetrapyrrole,
- term:
    id: GO:0006780
    label: uroporphyrinogen III biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Electronic transfer of the immediate biosynthetic process from the rat
      ortholog; correct.
    action: ACCEPT
    reason: Matches the enzyme's direct product; concordant with human experimental
      annotations to the same term.
    supported_by:
    - reference_id: PMID:3174619
      supporting_text: the cyclic tetrapyrrole, uroporphyrinogen III
- term:
    id: GO:0070541
    label: response to platinum ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: Peripheral response term derived from expression-type ortholog data;
      does not reflect the enzyme's biosynthetic function and is not core.
    supported_by:
    - reference_id: file:human/UROS/UROS-uniprot.txt
      supporting_text: Catalyzes cyclization of the linear tetrapyrrole,
- term:
    id: GO:0071243
    label: cellular response to arsenic-containing substance
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Generic response term electronically transferred from the rat ortholog;
      not a characterized function of human UROS.
    action: MARK_AS_OVER_ANNOTATED
    reason: Peripheral perturbation-response annotation from ortholog transfer, not
      the enzyme's core biosynthetic role.
    supported_by:
    - reference_id: file:human/UROS/UROS-uniprot.txt
      supporting_text: Catalyzes cyclization of the linear tetrapyrrole,
- term:
    id: GO:0071418
    label: cellular response to amine stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Generic response term electronically transferred from the rat ortholog;
      not a characterized function of human UROS.
    action: MARK_AS_OVER_ANNOTATED
    reason: Peripheral perturbation-response annotation from ortholog transfer, not
      the enzyme's core biosynthetic role.
    supported_by:
    - reference_id: file:human/UROS/UROS-uniprot.txt
      supporting_text: Catalyzes cyclization of the linear tetrapyrrole,
- term:
    id: GO:0006785
    label: heme B biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:18004775
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: The experimental support establishes UROS's role in heme/porphyrin
      biosynthesis, but the heme-b-specific term is over-specific for a branch-point
      enzyme; the general heme biosynthetic process (GO:0006783), also annotated, is
      the appropriate representation. Retained rather than removed per the underlying
      experimental evidence.
    supported_by:
    - reference_id: PMID:18004775
      supporting_text: cutaneous disorder, congenital erythropoietic porphyria
- term:
    id: GO:0006783
    label: heme biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-189451
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Core biological process for this enzyme; well supported by literature and
      the Reactome heme biosynthesis pathway.
    supported_by:
    - reference_id: Reactome:R-HSA-189451
      supporting_text: The next two steps convert four molecules of PBG into the cyclic
        tetrapyrrole uroporphyringen III
- term:
    id: GO:0004852
    label: uroporphyrinogen-III synthase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-189488
  qualifier: enables
  review:
    summary: Reactome-curated statement of the core catalytic activity (HMB to
      uroporphyrinogen III).
    action: ACCEPT
    reason: Correct core molecular function, concordant with experimental evidence.
    supported_by:
    - reference_id: Reactome:R-HSA-189488
      supporting_text: catalyzes the conversion of HMB (hydroxymethylbilane) to uroporphyrinogen
        III, a reaction involving ring
- term:
    id: GO:0004852
    label: uroporphyrinogen-III synthase activity
  evidence_type: EXP
  original_reference_id: PMID:11689424
  qualifier: enables
  review:
    summary: Experimental (crystal structure with catalytic activity/mutagenesis)
      confirmation of the uroporphyrinogen-III synthase activity, including the ring
      closure with D-ring flipping.
    action: ACCEPT
    reason: Direct experimental support for the defining molecular function.
    supported_by:
    - reference_id: PMID:11689424
      supporting_text: catalyzes ring closure of the linear tetrapyrrole hydroxymethylbilane
        (HMB), with concurrent flipping of the D ring
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: is_active_in
  review:
    summary: Cytosolic localization inferred by sequence similarity to the mouse
      ortholog; consistent with the curated human localization.
    action: ACCEPT
    reason: Correct location; concordant with UniProt and Reactome.
    supported_by:
    - reference_id: file:human/UROS/UROS-uniprot.txt
      supporting_text: Cytoplasm, cytosol
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-189488
  qualifier: located_in
  review:
    summary: Reactome places the UROS reaction in the cytosol.
    action: ACCEPT
    reason: Correct location, consistent with the four cytosolic steps of heme
      biosynthesis.
    supported_by:
    - reference_id: file:human/UROS/UROS-uniprot.txt
      supporting_text: Cytoplasm, cytosol
- term:
    id: GO:0006783
    label: heme biosynthetic process
  evidence_type: IC
  original_reference_id: PMID:18004775
  qualifier: involved_in
  review:
    summary: Curator inference (from the GO:0004852 molecular function) that UROS
      participates in heme biosynthesis.
    action: ACCEPT
    reason: Sound inference; UROS is the fourth enzyme of the heme biosynthetic
      pathway and this is a core biological process.
    supported_by:
    - reference_id: PMID:11689424
      supporting_text: the fourth enzyme in the porphyrin biosynthetic pathway
- term:
    id: GO:0004852
    label: uroporphyrinogen-III synthase activity
  evidence_type: IDA
  original_reference_id: PMID:3805019
  qualifier: enables
  review:
    summary: The enzyme was purified to homogeneity from human erythrocytes and shown
      to form uroporphyrinogen III from hydroxymethylbilane, directly demonstrating
      uroporphyrinogen-III synthase activity.
    action: ACCEPT
    reason: Direct experimental demonstration of the core catalytic activity.
    supported_by:
    - reference_id: PMID:3805019
      supporting_text: the purified enzyme formed uroporphyrinogen
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    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.
    action: REMOVE
    reason: Contradicted by the curated cytosolic localization; a non-experimental
      ISS inference that is inconsistent with current UniProt and pathway evidence.
    supported_by:
    - reference_id: file:human/UROS/UROS-uniprot.txt
      supporting_text: Cytoplasm, cytosol
    - reference_id: PMID:18004775
      supporting_text: cytosolic enzymes of heme biosynthesis
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: NAS
  original_reference_id: PMID:3805019
  qualifier: located_in
  review:
    summary: Non-traceable author statement of cytosolic localization; the enzyme was
      purified from human erythrocyte cytosol.
    action: ACCEPT
    reason: Consistent with the well-established cytosolic localization of UROS.
    supported_by:
    - reference_id: file:human/UROS/UROS-uniprot.txt
      supporting_text: Cytoplasm, cytosol
- term:
    id: GO:0006780
    label: uroporphyrinogen III biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:3805019
  qualifier: involved_in
  review:
    summary: The purified enzyme formed uroporphyrinogen III from hydroxymethylbilane,
      directly demonstrating its role in uroporphyrinogen III biosynthesis.
    action: ACCEPT
    reason: Direct experimental support for the immediate biosynthetic process.
    supported_by:
    - reference_id: PMID:3805019
      supporting_text: the purified enzyme formed uroporphyrinogen
- term:
    id: GO:0006783
    label: heme biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:3805019
  qualifier: involved_in
  review:
    summary: The paper characterizes UROS as the fourth enzyme in the heme
      biosynthetic pathway, purified from human erythrocytes.
    action: ACCEPT
    reason: Core biological process; UROS is an essential heme-biosynthesis enzyme.
    supported_by:
    - reference_id: PMID:3805019
      supporting_text: the fourth enzyme in the heme biosynthetic pathway
- term:
    id: GO:0004852
    label: uroporphyrinogen-III synthase activity
  evidence_type: IDA
  original_reference_id: PMID:18004775
  qualifier: enables
  review:
    summary: NMR active-site mapping study of URO-synthase confirming the enzyme
      catalyzes cyclization and D-ring isomerization of hydroxymethylbilane to
      uroporphyrinogen III.
    action: ACCEPT
    reason: Direct experimental support for the core catalytic activity.
    supported_by:
    - reference_id: PMID:11689424
      supporting_text: catalyzes ring closure of the linear tetrapyrrole hydroxymethylbilane
        (HMB), with concurrent flipping of the D ring
- term:
    id: GO:0006780
    label: uroporphyrinogen III biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:18004775
  qualifier: involved_in
  review:
    summary: The enzyme catalyzes the formation of uroporphyrinogen III from
      hydroxymethylbilane, directly implicating it in uroporphyrinogen III
      biosynthesis.
    action: ACCEPT
    reason: Direct experimental support for the immediate biosynthetic process.
    supported_by:
    - reference_id: PMID:11689424
      supporting_text: catalyzes ring closure of the linear tetrapyrrole hydroxymethylbilane
        (HMB), with concurrent flipping of the D ring
- term:
    id: GO:0004852
    label: uroporphyrinogen-III synthase activity
  evidence_type: IDA
  original_reference_id: PMID:3174619
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Direct experimental support (functional expression) for the core catalytic
      activity.
    supported_by:
    - reference_id: PMID:3174619
      supporting_text: the fourth enzyme in the heme biosynthetic pathway
- term:
    id: GO:0006780
    label: uroporphyrinogen III biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:3174619
  qualifier: involved_in
  review:
    summary: The cloned/expressed enzyme is responsible for conversion of
      hydroxymethylbilane to uroporphyrinogen III.
    action: ACCEPT
    reason: Direct experimental support for the immediate biosynthetic process.
    supported_by:
    - reference_id: PMID:3174619
      supporting_text: the cyclic tetrapyrrole, uroporphyrinogen III
core_functions:
- description: 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.
  molecular_function:
    id: GO:0004852
    label: uroporphyrinogen-III synthase activity
  directly_involved_in:
  - id: GO:0006783
    label: heme biosynthetic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:11689424
    supporting_text: catalyzes ring closure of the linear tetrapyrrole hydroxymethylbilane
      (HMB), with concurrent flipping of the D ring
  - reference_id: PMID:3805019
    supporting_text: the fourth enzyme in the heme biosynthetic pathway
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11689424
  title: Crystal structure of human uroporphyrinogen III synthase.
  findings:
  - statement: Human U3S catalyzes ring closure of the linear tetrapyrrole
      hydroxymethylbilane with concurrent flipping of the D ring to form
      uroporphyrinogen III; it is the fourth enzyme of the porphyrin biosynthetic
      pathway and exists as a monomer.
    supporting_text: catalyzes ring closure of the linear tetrapyrrole hydroxymethylbilane
      (HMB), with concurrent flipping of the D ring
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified crystal-structure paper for human UROS; full text
      cached; directly establishes catalytic activity, D-ring flipping, monomeric
      state, and CEP relevance.
- id: PMID:18004775
  title: 'Human uroporphyrinogen III synthase: NMR-based mapping of the active site.'
  findings:
  - statement: URO-synthase catalyzes the cyclization and D-ring isomerization of
      hydroxymethylbilane to uroporphyrinogen III; it is a cytosolic enzyme of heme
      biosynthesis whose deficiency causes congenital erythropoietic porphyria.
    supporting_text: cytosolic enzymes of heme biosynthesis
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; abstract-only in cache but foregrounds catalytic
      cyclization/D-ring isomerization and cytosolic localization for human UROS.
- id: PMID:3174619
  title: 'Human uroporphyrinogen III synthase: molecular cloning, nucleotide sequence,
    and expression of a full-length cDNA.'
  findings:
  - statement: Cloning and E. coli expression of full-length human URO-synthase cDNA
      encoding a 265-aa protein; the enzyme is the fourth enzyme of the heme
      biosynthetic pathway that converts hydroxymethylbilane to uroporphyrinogen III.
    supporting_text: the cyclic tetrapyrrole, uroporphyrinogen III
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified original cloning paper; abstract-only in cache but
      establishes gene identity and function.
- id: PMID:3805019
  title: Purification and properties of uroporphyrinogen III synthase from human erythrocytes.
  findings:
  - statement: UROS was purified to homogeneity from human erythrocytes and, using
      hydroxymethylbilane as substrate, formed uroporphyrinogen III without
      hydroxymethylbilane synthase or other cofactors; the enzyme is a monomer.
    supporting_text: the purified enzyme formed uroporphyrinogen
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified biochemical characterization; abstract-only in cache
      but directly supports catalytic activity and monomeric cytosolic state.
- id: Reactome:R-HSA-189451
  title: Heme biosynthesis
  findings:
  - statement: Heme biosynthesis proceeds via eight enzymes, four in the cytosol;
      four molecules of PBG are converted into the cyclic tetrapyrrole
      uroporphyrinogen III.
    supporting_text: The next two steps convert four molecules of PBG into the cyclic
      tetrapyrrole uroporphyringen III
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reactome pathway placing UROS among the cytosolic heme-biosynthesis
      steps.
- id: Reactome:R-HSA-189488
  title: UROS transforms HMB to URO3
  findings:
  - statement: Cytosolic UROS catalyzes conversion of hydroxymethylbilane to
      uroporphyrinogen III via ring closure and intramolecular rearrangement;
      uroporphyrinogen III is the branch point for heme, chlorophyll and corrins.
    supporting_text: catalyzes the conversion of HMB (hydroxymethylbilane) to uroporphyrinogen
      III, a reaction involving ring
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reactome reaction entry for the UROS-catalyzed step.
- id: file:human/UROS/UROS-uniprot.txt
  title: UniProtKB entry P10746 (HEM4_HUMAN), Uroporphyrinogen-III synthase
  findings:
  - statement: UROS catalyzes cyclization of the linear tetrapyrrole
      hydroxymethylbilane to the macrocyclic uroporphyrinogen III, the branch point
      for the porphyrin sub-pathways; it is a cytosolic monomer, and deficiency
      causes congenital erythropoietic porphyria with non-enzymatic conversion of
      hydroxymethylbilane to the uroporphyrinogen-I isomer.
    supporting_text: Catalyzes cyclization of the linear tetrapyrrole,
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Curated UniProt record; source for function, catalytic activity,
      cytosolic localization, monomeric state, and CEP disease association.