UROC1

Gene Description

UROC1 encodes urocanate hydratase (urocanase; EC 4.2.1.49), the enzyme that catalyzes the second step of L-histidine catabolism. It hydrates trans-urocanate to 4-imidazolone-5-propanoate, using a tightly bound NAD+ as an electrophilic cofactor that adds to the substrate to activate it for hydration and is regenerated each catalytic cycle (rather than acting as a redox coenzyme). The reaction follows histidase (HAL)-catalyzed deamination of L-histidine to urocanate and precedes imidazolonepropionase (AMDHD1) and formiminotransferase (FTCD) steps, so that histidine is ultimately degraded to L-glutamate. The protein is a cytosolic enzyme of the conserved urocanase family with a Rossmann-like NAD-binding fold, and is highly expressed in liver, the principal site of histidine catabolism. Loss of urocanase activity causes urocanase deficiency (urocanic aciduria), an inborn error of histidine metabolism associated with neurological features including intellectual disability and ataxia.

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0016153 urocanate hydratase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred urocanate hydratase activity. This is the well-established core catalytic function of UROC1 (EC 4.2.1.49) and matches the UniProt RecName, the annotated catalytic reaction, and the experimental IDA on the same term. Correct and core. Supporting Evidence: file:human/UROC1/UROC1-uniprot.txt RecName: Full=Urocanate hydratase;
GO:0006548 L-histidine catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred involvement in L-histidine catabolism. UROC1 catalyzes step 2 of the histidine degradation pathway (urocanate -> 4-imidazolone-5-propanoate), and loss of function causes urocanic aciduria. Correct and core; also independently supported by the experimental IMP. Supporting Evidence: file:human/UROC1/UROC1-uniprot.txt Amino-acid degradation; L-histidine degradation into L-
GO:0016153 urocanate hydratase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation of urocanate hydratase activity derived from InterPro family membership and the RHEA/EC mapping (RHEA:13101, EC:4.2.1.49). This correctly recapitulates the core catalytic function and is redundant with the experimental IDA and the IBA on the same term. Supporting Evidence: file:human/UROC1/UROC1-uniprot.txt EC=4.2.1.49;
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from a single high-throughput yeast two-hybrid hit (HuRI reference interactome) reporting a UROC1-ALX1 (Q15699) interaction. The term is uninformative and the pairing of a cytosolic histidine-catabolic enzyme with a homeodomain transcription factor has no established biological meaning; it is not part of UROC1's core function. Per policy the experimental IPI is retained but flagged as an over-annotation rather than removed. Supporting Evidence: PMID:32296183 With approximately 53,000 protein-protein interactions, HuRI has approximately four times as many such interactions
GO:0005829 cytosol	TAS Reactome:R-HSA-70903	ACCEPT	Summary: Cytosolic localization asserted by Reactome, which designates UROC1 as the cytosolic urocanate hydratase catalyzing urocanate + H2O -> 4-imidazolone-5-propanoate. Consistent with the experimental IDA to the same term. Correct core localization. Supporting Evidence: Reactome:R-HSA-70903 Cytosolic urocanate hydratase (UROC1) catalyzes the hydrolysis of urocanate to form 4-imidazolone-5-propanoate.
GO:0005829 cytosol	IDA PMID:19304569 Mutations in the urocanase gene UROC1 are associated with ur...	ACCEPT	Summary: Direct-assay cytosolic localization from the Espinós et al. study of UROC1 in urocanic aciduria, which performed protein expression and enzyme activity studies on urocanase. Cytosol is the expected and correct compartment for this histidine-catabolic enzyme; core localization. Supporting Evidence: PMID:19304569 protein expression studies and enzyme activity assays suggest that none of the mutations
GO:0006548 L-histidine catabolic process	IMP PMID:19304569 Mutations in the urocanase gene UROC1 are associated with ur...	ACCEPT	Summary: Involvement in L-histidine catabolism supported by mutation/phenotype evidence: biallelic UROC1 variants (p.L70P, p.R450C) cause urocanic aciduria, an inborn error of histidine metabolism, with functional assays showing loss of a fully active enzyme. This is the core biological process for UROC1. Supporting Evidence: PMID:19304569 the first putative mutations, p.L70P and p.R450C, in the coding region of the UROC1 gene in a girl with urocanic aciduria
GO:0016153 urocanate hydratase activity	IDA PMID:19304569 Mutations in the urocanase gene UROC1 are associated with ur...	ACCEPT	Summary: Direct-assay urocanate hydratase activity: Espinós et al. measured urocanase enzyme activity for wild-type and patient variants, confirming UROC1's catalytic function in vivo (variants abolish activity). This is the primary experimental support for the core molecular function. Supporting Evidence: PMID:19304569 enzyme activity assays suggest that none of the mutations can produce a fully functional enzyme
GO:0051287 NAD binding	NAS file:human/UROC1/UROC1-uniprot.txt	NEW	Summary: Proposed new annotation. Urocanate hydratase uses a tightly bound NAD+ as an electrophilic cofactor (not a redox coenzyme); UniProt annotates NAD(+) as the cofactor and multiple conserved NAD(+)-binding residues by similarity to bacterial urocanase. NAD binding is a core molecular function absent from GOA. Supporting Evidence: file:human/UROC1/UROC1-uniprot.txt Name=NAD(+); Xref=ChEBI:CHEBI:57540; Evidence={ECO:0000250};

Core Functions

Urocanate hydratase (urocanase) activity: hydration of trans-urocanate to 4-imidazolone-5-propanoate, the second step of L-histidine catabolism, using a tightly bound NAD+ as an electrophilic cofactor.

Molecular Function:

urocanate hydratase activity

Supporting Evidence:

PMID:19304569
enzyme activity assays suggest that none of the mutations can produce a fully functional enzyme
file:human/UROC1/UROC1-uniprot.txt
Reaction=4-imidazolone-5-propanoate = trans-urocanate + H2O;

Binding of NAD+, which is retained as a tightly bound electrophilic cofactor required for urocanate hydratase catalysis (conserved NAD-binding residues and the urocanase-family Rossmann-like fold).

Molecular Function:

NAD binding

Supporting Evidence:

file:human/UROC1/UROC1-uniprot.txt
Name=NAD(+); Xref=ChEBI:CHEBI:57540; Evidence={ECO:0000250};

Participation in L-histidine catabolism (histidine degradation to glutamate) in the cytosol, where UROC1 acts downstream of histidase to hydrate urocanate; loss of function causes urocanic aciduria.

Molecular Function:

urocanate hydratase activity

Cellular Locations:

cytosol

Supporting Evidence:

PMID:19304569
the first putative mutations, p.L70P and p.R450C, in the coding region of the UROC1 gene in a girl with urocanic aciduria

Gene Description

Existing Annotations Review

Core Functions

Urocanate hydratase (urocanase) activity: hydration of trans-urocanate to 4-imidazolone-5-propanoate, the second step of L-histidine catabolism, using a tightly bound NAD+ as an electrophilic cofactor.

Binding of NAD+, which is retained as a tightly bound electrophilic cofactor required for urocanate hydratase catalysis (conserved NAD-binding residues and the urocanase-family Rossmann-like fold).

Participation in L-histidine catabolism (histidine degradation to glutamate) in the cytosol, where UROC1 acts downstream of histidase to hydrate urocanate; loss of function causes urocanic aciduria.

References

📚 Additional Documentation

Notes

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