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: PAINT IBA (GO_REF:0000033) within PANTHER family PTHR11557 (porphobilinogen deaminase). HMBS itself catalyzes the third step of heme biosynthesis (PBG to hydroxymethylbilane), so this is catalytic participation; consistent with the experimental and structural literature. Core process. Supporting Evidence: PMID:23815679 (porphobilinogen) deaminase], the third enzyme in the haem biosynthesis pathway. file:human/HMBS/HMBS-uniprot.txt As part of the heme biosynthetic pathway, catalyzes the sequential polymerization of four molecules of porphobilinogen to form hydroxymethylbilane, also known as preuroporphyrinogen file:human/HMBS/HMBS-uniprot.txt PANTHER; PTHR11557; PORPHOBILINOGEN DEAMINASE; 1.
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: PAINT IBA (GO_REF:0000033) from PTHR11557. The family's defining activity, strongly supported by kinetic and structural work on 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 preuroporphyrin file:human/HMBS/HMBS-uniprot.txt Reaction=4 porphobilinogen + H2O = hydroxymethylbilane + 4 NH4(+) file:human/HMBS/HMBS-uniprot.txt PANTHER; PTHR11557; PORPHOBILINOGEN DEAMINASE; 1.
GO:0005737 cytoplasm	IBA GO_REF:0000033	MODIFY	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 but general. HMBS is a soluble enzyme of the cytosolic phase of heme synthesis, so the specific descendant cytosol (GO:0005829), already carried by the gene (IEA, ISS, TAS), is the appropriate replacement for this PAINT IBA (PTHR11557). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000168159 SUPPORTS TRANSFER The ancestral cytoplasm assertion is compatible with the human cytosolic enzyme; the replacement only adds compartment precision. Proposed replacements: cytosol Supporting Evidence: file:human/HMBS/HMBS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol Reactome:R-HSA-189406 Cytosolic porphobilinogen deaminase catalyzes the polymerization of four molecules of porphobilinogen (PBG) to generate hydroxymethylbilane (HMB), an unstable tetrapyrrole. file:human/HMBS/HMBS-uniprot.txt PANTHER; PTHR11557; PORPHOBILINOGEN DEAMINASE; 1.
GO:0004418 hydroxymethylbilane synthase activity	IEA GO_REF:0000120	ACCEPT	Summary: Combined automated electronic annotation (GO_REF:0000120; family signatures and the EC/Rhea catalytic-activity annotation) of hydroxymethylbilane synthase activity. Reason: Correct core catalytic function; the curated catalytic-activity line rests on experiments on the human enzyme, and the HAMAP/InterPro signatures place the protein in the porphobilinogen deaminase family. Supporting Evidence: file:human/HMBS/HMBS-uniprot.txt Reaction=4 porphobilinogen + H2O = hydroxymethylbilane + 4 NH4(+) file:human/HMBS/HMBS-uniprot.txt HAMAP; MF_00260; Porphobil_deam; 1. file:human/HMBS/HMBS-uniprot.txt InterPro; IPR000860; HemC.
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 Reactome:R-HSA-189406 Cytosolic porphobilinogen deaminase catalyzes the polymerization of four molecules of porphobilinogen (PBG) to generate hydroxymethylbilane (HMB), an unstable tetrapyrrole.
GO:0006779 porphyrin-containing compound biosynthetic process	IEA GO_REF:0000117	MODIFY	Summary: ARBA electronic annotation (GO_REF:0000117) to porphyrin-containing compound biosynthetic process. Reason: Correct but more general than the evidence supports. In human cells the hydroxymethylbilane made by HMBS is committed to heme synthesis, so the specific descendant heme biosynthetic process (GO:0006783), already carried by the gene, is the appropriate replacement. The ARBA rule itself is not evidence. Proposed replacements: heme biosynthetic process Supporting Evidence: file:human/HMBS/HMBS-uniprot.txt As part of the heme biosynthetic pathway, catalyzes the sequential polymerization of four molecules of porphobilinogen to form hydroxymethylbilane, also known as preuroporphyrinogen PMID:23815679 (porphobilinogen) deaminase], the third enzyme in the haem biosynthesis pathway.
GO:0033014 tetrapyrrole biosynthetic process	IEA GO_REF:0000002	MODIFY	Summary: InterPro2GO electronic annotation (GO_REF:0000002) to tetrapyrrole biosynthetic process. Reason: Correct but more general than the evidence supports. Humans make no chlorophyll or cobalamin, so the tetrapyrrole pathway HMBS serves is heme biosynthesis; the specific descendant heme biosynthetic process (GO:0006783), already carried by the gene, is the appropriate replacement. Proposed replacements: heme biosynthetic process Supporting Evidence: PMID:23815679 The enzyme catalyses the assembly of four PBG molecules into the linear precursor of uroporphyrinogen III, HMB (hydroxymethylbilane, also called preuroporphyrin file:human/HMBS/HMBS-uniprot.txt As part of the heme biosynthetic pathway, catalyzes the sequential polymerization of four molecules of porphobilinogen to form hydroxymethylbilane, also known as preuroporphyrinogen file:human/HMBS/HMBS-uniprot.txt InterPro; IPR000860; HemC.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	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: Bare protein binding from a proteome-scale yeast two-hybrid interactome carries no functional information about HMBS; per the protein-binding policy the row is removed. Removal does not mean the reported interaction is false, and no partner implies a more informative HMBS molecular function. Supporting Evidence: PMID:32296183 reference interactome map of human binary protein interactions, or 'HuRI'.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	REMOVE	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: Bare protein binding from a proteome-scale yeast two-hybrid interactome carries no functional information about HMBS; per the protein-binding policy the row is removed. Removal does not mean the reported interaction is false, and no partner implies a more informative HMBS molecular function. Supporting Evidence: PMID:32814053 Here, we report on an interactome map that focuses on neurodegenerative disease (ND), connects ∼5,000 human proteins via ∼30,000 candidate interactions and is generated by systematic yeast two-hybrid interaction screening of ∼500 ND-related proteins and integration of literature interactions.
GO:0006785 heme B biosynthetic process	IDA PMID:18004775 Human uroporphyrinogen III synthase: NMR-based mapping of th...	ACCEPT	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: Correct and specific. Heme B (protoheme) is the end product of the pathway in which HMBS performs the third catalytic step, and the process term covers all steps 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 an efficient expression and purification procedure was developed for these cytosolic enzymes of heme biosynthesis file:human/HMBS/HMBS-uniprot.txt As part of the heme biosynthetic pathway, catalyzes the sequential polymerization of four molecules of porphobilinogen to form hydroxymethylbilane, also known as preuroporphyrinogen
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: Reactome:R-HSA-189406 Cytosolic porphobilinogen deaminase catalyzes the polymerization of four molecules of porphobilinogen (PBG) to generate hydroxymethylbilane (HMB), an unstable tetrapyrrole. PMID:23815679 (porphobilinogen) deaminase], 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: Reactome:R-HSA-189406 Cytosolic porphobilinogen deaminase catalyzes the polymerization of four molecules of porphobilinogen (PBG) to generate hydroxymethylbilane (HMB), an unstable tetrapyrrole. file:human/HMBS/HMBS-uniprot.txt Reaction=4 porphobilinogen + H2O = hydroxymethylbilane + 4 NH4(+)
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 Recombinant p.R32P was enzymatically inactive as demonstrated by a <1% residual activity, whereas p.D178N possessed 81% of the activity of the wild type enzyme. file:human/HMBS/HMBS-uniprot.txt Reaction=4 porphobilinogen + H2O = hydroxymethylbilane + 4 NH4(+)
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 preuroporphyrin file:human/HMBS/HMBS-uniprot.txt KM=48 uM for porphobilinogen {ECO:0000269\|PubMed:23815679}
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 Reactome:R-HSA-189406 Cytosolic porphobilinogen deaminase catalyzes the polymerization of four molecules of porphobilinogen (PBG) to generate hydroxymethylbilane (HMB), an unstable tetrapyrrole.
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 Reduced activity of the enzyme porphobilinogen deaminase (PBGD), which catalyzes the sequential condensation of 4 molecules of porphobilinogen to yield preuroporphyrinogen, has been linked to the symptoms of AIP. PMID:18936296 Analysis of the structure revealed a dipyrromethane cofactor molecule covalently linked to C261, sitting in a positively charged cleft region. PMID:18936296 H120P mutation resulted in an inactive enzyme, supporting the role of H120 as a hinge residue.
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 Reduced activity of the enzyme porphobilinogen deaminase (PBGD), which catalyzes the sequential condensation of 4 molecules of porphobilinogen to yield preuroporphyrinogen, has been linked to the symptoms of AIP. file:human/HMBS/HMBS-uniprot.txt As part of the heme biosynthetic pathway, catalyzes the sequential polymerization of four molecules of porphobilinogen to form hydroxymethylbilane, also known as 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: Reactome:R-HSA-189406 Cytosolic porphobilinogen deaminase catalyzes the polymerization of four molecules of porphobilinogen (PBG) to generate hydroxymethylbilane (HMB), an unstable tetrapyrrole. 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 an efficient expression and purification procedure was developed for these cytosolic enzymes of heme biosynthesis file:human/HMBS/HMBS-uniprot.txt As part of the heme biosynthetic pathway, catalyzes the sequential polymerization of four molecules of porphobilinogen to form hydroxymethylbilane, also known as preuroporphyrinogen
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 The absence of chemical shift changes in the (15)N spectrum of URO-synthase mixed with the homogeneous HMB-synthase holoenzyme or URO-decarboxylase precluded occurrence of a stable cytosolic enzyme complex. file:human/HMBS/HMBS-uniprot.txt Reaction=4 porphobilinogen + H2O = hydroxymethylbilane + 4 NH4(+)
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: Traceable author statement citing mechanistic mutagenesis of the Escherichia coli enzyme, which shows conserved arginines bind the dipyrromethane cofactor and growing oligopyrrole chain. The cited work is on the bacterial ortholog, but the activity it characterizes is the same conserved hydroxymethylbilane synthase activity demonstrated directly for human HMBS; accepted. Supporting Evidence: PMID:2025226 The kinetic parameters for these mutant enzymes and studies on the formation of intermediate enzyme-substrate complexes indicate that several of these arginine residues are involved in binding the carboxylate side chains of the pyrromethane cofactor and the growing oligopyrrole chain. file:human/HMBS/HMBS-uniprot.txt Reaction=4 porphobilinogen + H2O = hydroxymethylbilane + 4 NH4(+)

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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