HMBS

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006783 heme biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) annotation placing HMBS in the heme biosynthetic process. This is a core biological process for HMBS, which catalyzes the third step of heme synthesis in the cytosol. Reason: HMBS/PBGD is a canonical heme biosynthesis enzyme; the IBA annotation is consistent with experimental and structural literature and with UniProt. Supporting Evidence: PMID:23815679 the third enzyme in the haem biosynthesis pathway file:human/HMBS/HMBS-uniprot.txt As part of the heme biosynthetic pathway, catalyzes the
GO:0004418 hydroxymethylbilane synthase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) annotation of the diagnostic molecular function, hydroxymethylbilane synthase (porphobilinogen deaminase) activity. This is the core catalytic function of HMBS. Reason: Well conserved across the HMBS family and strongly supported by experimental and structural data in human HMBS. Supporting Evidence: PMID:23815679 The enzyme catalyses the assembly of four PBG molecules into the linear precursor of uroporphyrinogen III, HMB (hydroxymethylbilane, also called preuroporphyrinogen)
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) annotation to cytoplasm. HMBS is a soluble cytosolic enzyme; cytoplasm is correct but is a broader parent of the more precise cytosol location. Reason: Correct localization, though less specific than the cytosol annotations also present. Retained as a valid (parent-level) location. Supporting Evidence: file:human/HMBS/HMBS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol PMID:18004775 cytosolic enzymes of heme biosynthesis
GO:0004418 hydroxymethylbilane synthase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation of hydroxymethylbilane synthase activity via combined IEA methods (InterPro/ARBA/RHEA/EC:2.5.1.61). Matches the experimentally established function. Reason: The EC 2.5.1.61 / RHEA:13185 mapping is exactly the reaction HMBS catalyzes; the electronic call is correct and specific. Supporting Evidence: file:human/HMBS/HMBS-uniprot.txt EC=2.5.1.61
GO:0005829 cytosol	IEA GO_REF:0000044	ACCEPT	Summary: Electronic annotation to cytosol from the UniProt subcellular-location keyword mapping. This is the precise cellular location of HMBS. Reason: Consistent with UniProt SUBCELLULAR LOCATION (Cytoplasm, cytosol) and with the Reactome description of cytosolic PBG deaminase. Core location. Supporting Evidence: file:human/HMBS/HMBS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0006779 porphyrin-containing compound biosynthetic process	IEA GO_REF:0000117	ACCEPT	Summary: ARBA electronic annotation to porphyrin-containing compound biosynthetic process. Correct but more general than the specific heme biosynthetic process. Reason: HMBS participates in porphyrin/tetrapyrrole biosynthesis; the parent-level term is accurate. Kept as a broader, still-correct annotation. Supporting Evidence: file:human/HMBS/HMBS-uniprot.txt Porphyrin-containing compound metabolism
GO:0033014 tetrapyrrole biosynthetic process	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO electronic annotation to tetrapyrrole biosynthetic process. HMBS builds the linear tetrapyrrole hydroxymethylbilane, so this is correct, though broader than heme biosynthesis. Reason: The reaction product is a tetrapyrrole; the parent-level BP term is accurate. Retained as a broader, still-correct annotation. Supporting Evidence: PMID:23815679 The enzyme catalyses the assembly of four PBG molecules into the linear precursor of uroporphyrinogen III, HMB (hydroxymethylbilane, also called preuroporphyrinogen)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: IPI "protein binding" from a high-throughput human binary-interactome (Y2H) screen, recording an interaction with PICK1 (UniProtKB:Q9NRD5). Bare "protein binding" is uninformative about HMBS function. Reason: The interaction is from a proteome-scale binary-interactome map; the generic "protein binding" term conveys no specific molecular function for HMBS and no dedicated biological role for this interaction is established. Per curation policy the experimental IPI is retained but flagged as over-annotated rather than removed. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: IPI "protein binding" from a neurodegenerative-disease interactome mapping study, recording an interaction with huntingtin (HTT, UniProtKB:P42858). Bare "protein binding" is uninformative about HMBS function. Reason: The interaction comes from a large interactome-mapping effort focused on neurodegenerative-disease proteins; the generic term does not describe a specific HMBS molecular function. Per curation policy the experimental IPI is retained but flagged as over-annotated rather than removed. Supporting Evidence: PMID:32814053 Network of Neurodegenerative Disease Proteins
GO:0006785 heme B biosynthetic process	IDA PMID:18004775 Human uroporphyrinogen III synthase: NMR-based mapping of th...	MARK AS OVER ANNOTATED	Summary: IDA annotation to the specific process "heme B biosynthetic process". HMBS contributes to heme biosynthesis broadly, but its direct step (producing the linear tetrapyrrole hydroxymethylbilane) is several steps upstream of heme b formation. Reason: HMBS makes hydroxymethylbilane, a precursor common to all downstream tetrapyrroles; attributing specifically "heme B biosynthetic process" is more specific than the enzyme's direct chemistry warrants and the generic heme biosynthetic process (also annotated) captures its role better. The IDA reference is an experimental study of cytosolic heme-biosynthesis enzymes; the experimental annotation is retained (not removed) but flagged as over-specific/over-annotated. Supporting Evidence: PMID:18004775 cytosolic enzymes of heme biosynthesis
GO:0006783 heme biosynthetic process	TAS Reactome:R-HSA-189451	ACCEPT	Summary: Reactome TAS annotation (Heme biosynthesis pathway) to heme biosynthetic process. Core biological process for HMBS. Reason: Reactome authoritatively places cytosolic PBG deaminase in the heme biosynthesis pathway; consistent with all other evidence. Supporting Evidence: PMID:23815679 the third enzyme in the haem biosynthesis pathway
GO:0004418 hydroxymethylbilane synthase activity	TAS Reactome:R-HSA-189406	ACCEPT	Summary: Reactome TAS annotation (reaction "4 PBGs bind to form HMB") of hydroxymethylbilane synthase activity. Core catalytic function. Reason: Directly describes the HMBS-catalyzed reaction (polymerization of four PBG to form HMB); fully consistent with experimental data. Supporting Evidence: PMID:18936296 which catalyzes the sequential condensation of 4 molecules of porphobilinogen to yield preuroporphyrinogen
GO:0004418 hydroxymethylbilane synthase activity	EXP PMID:19138865 Correlation between biochemical findings, structural and enz...	ACCEPT	Summary: Experimental (EXP) annotation of HMBS activity based on recombinant expression and enzyme-activity assays of wild-type and AIP-mutant HMBS. Core catalytic function. Reason: The study directly measures HMBS enzymatic activity of recombinant human protein (e.g., R32P inactive, D178N ~81% of wild-type), confirming the molecular function. Supporting Evidence: PMID:19138865 Mutations in the hydroxymethylbilane synthase (HMBS) gene are responsible for the inherited disorder of acute intermittent porphyria
GO:0004418 hydroxymethylbilane synthase activity	EXP PMID:23815679 Conformational stability and activity analysis of two hydrox...	ACCEPT	Summary: Experimental (EXP) annotation of HMBS activity from enzyme-kinetic characterization of recombinant wild-type and mutant HMBS. Core catalytic function. Reason: Direct kinetic assays of recombinant human HMBS establish the hydroxymethylbilane synthase activity and its assembly of four PBG into HMB. Supporting Evidence: PMID:23815679 The enzyme catalyses the assembly of four PBG molecules into the linear precursor of uroporphyrinogen III, HMB (hydroxymethylbilane, also called preuroporphyrinogen)
GO:0005829 cytosol	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation to cytosol by sequence-similarity transfer from mouse (MGI). HMBS acts as a soluble cytosolic enzyme. Reason: Consistent with the experimentally supported cytosolic localization of HMBS and with UniProt. Supporting Evidence: file:human/HMBS/HMBS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0004418 hydroxymethylbilane synthase activity	IDA PMID:18936296 Structural insight into acute intermittent porphyria.	ACCEPT	Summary: IDA annotation of HMBS activity from the crystal structure and functional characterization of human PBGD, including the covalently bound dipyrromethane cofactor and active-site mutagenesis. Core catalytic function. Reason: Structural and mutagenesis data directly establish the hydroxymethylbilane synthase (PBGD) activity of human HMBS and the cofactor-primed mechanism. Supporting Evidence: PMID:18936296 covalently linked to C261, sitting in a positively charged PMID:18936296 Sequential entry of 4 pyrrole molecules into the active site
GO:0006783 heme biosynthetic process	IDA PMID:18936296 Structural insight into acute intermittent porphyria.	ACCEPT	Summary: IDA annotation placing HMBS in the heme biosynthetic process, based on the structural/functional study of human PBGD in the context of AIP (a disease of heme biosynthesis). Core biological process. Reason: The study characterizes HMBS as the PBGD step of heme biosynthesis; consistent with all other BP evidence. Supporting Evidence: PMID:18936296 which catalyzes the sequential condensation of 4 molecules of porphobilinogen to yield preuroporphyrinogen
GO:0005829 cytosol	TAS Reactome:R-HSA-189406	ACCEPT	Summary: Reactome TAS annotation to cytosol for the "4 PBGs bind to form HMB" reaction. Core location. Reason: Reactome explicitly describes cytosolic porphobilinogen deaminase; consistent with UniProt and the ISS/IEA cytosol annotations. Supporting Evidence: file:human/HMBS/HMBS-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: IC (inferred by curator) annotation to heme biosynthetic process, based on the hydroxymethylbilane synthase activity (with/from GO:0004418). Core biological process. Reason: The curator inference from the established MF to the heme-biosynthesis BP is sound; HMBS is a cytosolic heme-biosynthesis enzyme. Supporting Evidence: PMID:18004775 cytosolic enzymes of heme biosynthesis
GO:0004418 hydroxymethylbilane synthase activity	IDA PMID:18004775 Human uroporphyrinogen III synthase: NMR-based mapping of th...	ACCEPT	Summary: IDA annotation of hydroxymethylbilane synthase activity from a study of the cytosolic heme-biosynthesis enzymes (which expressed and characterized human HMB-synthase holoenzyme alongside URO-synthase). Core catalytic function. Reason: The study prepared and worked with human HMB-synthase holoenzyme; the experimental MF annotation is retained. Although the paper's title foregrounds URO-synthase, the full text also involves HMB-synthase, and the function is correct for HMBS, so it is accepted (deferring to the curator). Supporting Evidence: PMID:18004775 cytosolic enzymes of heme biosynthesis
GO:0004418 hydroxymethylbilane synthase activity	TAS PMID:2025226 Studies on the mechanism of hydroxymethylbilane synthase con...	ACCEPT	Summary: TAS annotation of hydroxymethylbilane synthase activity from a mechanistic study of the enzyme (role of conserved arginine residues in substrate binding). Core catalytic function. Reason: A classical mechanistic study of hydroxymethylbilane synthase supporting the molecular function (substrate/cofactor binding via conserved arginines). The work was done in E. coli enzyme by site-directed mutagenesis but establishes the conserved HMBS/PBGD activity; retained as TAS support for the MF. Supporting Evidence: PMID:2025226 The role of conserved arginine residues in hydroxymethylbilane synthase

Gene Description

Existing Annotations Review

Core Functions

Catalyzes the third step of heme biosynthesis: the sequential (head-to-tail) polymerization of four molecules of porphobilinogen into the linear tetrapyrrole hydroxymethylbilane (preuroporphyrinogen), using a covalently bound, self-derived dipyrromethane cofactor as a primer, in the cytosol.

References

📚 Additional Documentation

Notes

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