HMGCR

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004420 hydroxymethylglutaryl-CoA reductase (NADPH) activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) assignment of the defining molecular function of HMGCR: NADPH-dependent reduction of HMG-CoA to mevalonate. This is the well-established catalytic activity of the enzyme, supported by direct human enzymology and crystallography, and is the core function of the gene. Reason: Correct and specific. HMGCR is the rate-limiting enzyme of the mevalonate pathway; the IBA is corroborated by human experimental evidence. Supporting Evidence: PMID:10698924 catalyzes the formation of PMID:10698924 mevalonate, the committed step
GO:0005789 endoplasmic reticulum membrane	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic assignment placing HMGCR activity in the ER membrane, consistent with its being a polytopic ER membrane protein anchored by an N-terminal multi-pass membrane domain. Reason: ER membrane is the primary, well-established site of HMGCR; supported by human subcellular-location data and the multi-pass membrane topology in UniProt. Supporting Evidence: PMID:2991281 the membrane-bound glycoprotein that regulates cholesterol synthesis file:human/HMGCR/HMGCR-uniprot.txt Endoplasmic reticulum membrane
GO:0016126 sterol biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic assignment of HMGCR to sterol biosynthesis. As the rate-limiting step producing mevalonate, HMGCR is required for cholesterol/sterol synthesis. Reason: Accurate pathway assignment; mevalonate is the obligate precursor of sterols. Retained as a core biological process, alongside the more specific cholesterol biosynthetic process annotation. Supporting Evidence: PMID:10698924 the committed step in the biosynthesis of sterols and isoprenoids
GO:0008299 isoprenoid biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic assignment of HMGCR to isoprenoid biosynthesis. Mevalonate is the precursor of all non-sterol isoprenoids (dolichol, ubiquinone, prenyl groups) as well as sterols. Reason: Correct: HMGCR is the committed step producing mevalonate for both sterol and non-sterol isoprenoid branches. Supporting Evidence: PMID:10698924 the committed step in the biosynthesis of sterols and isoprenoids
GO:0005778 peroxisomal membrane	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic assignment of HMGCR to the peroxisomal membrane. A peroxisomal pool of pre-squalene mevalonate-pathway enzymes has been reported, but this localization is contested and secondary to the dominant ER membrane pool. Reason: Retained because there is experimental support for a peroxisomal pool of pre-squalene isoprenoid enzymes, but peroxisomal localization of these enzymes is disputed in the literature and is not the core site of HMGCR action, which is the ER membrane. Marked non-core rather than accepted as a primary location. Supporting Evidence: PMID:17180682 isoprenoid/cholesterol biosynthetic pathway occur in peroxisomes
GO:0004420 hydroxymethylglutaryl-CoA reductase (NADPH) activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (InterPro/EC/RHEA-based) assignment of the core catalytic activity. Redundant with the experimental and IBA annotations to the same term. Reason: Correct core molecular function, mapped from HMG-CoA reductase InterPro domains, EC 1.1.1.34 and RHEA:15989. Consistent with all experimental evidence. Supporting Evidence: file:human/HMGCR/HMGCR-uniprot.txt the rate-limiting step in the synthesis of
GO:0005778 peroxisomal membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: UniProt Subcellular-Location keyword mapping to peroxisomal membrane, reflecting the reported (contested) peroxisomal pool of pre-squalene isoprenoid enzymes. Reason: Consistent with the UniProt "Peroxisome membrane" subcellular location, itself based on PMID:17180682. Kept as a non-core location; the dominant and functionally central site of HMGCR is the ER membrane. Supporting Evidence: file:human/HMGCR/HMGCR-uniprot.txt Peroxisome membrane
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assignment of the primary ER membrane location, mapped from InterPro (metazoan HMGCR) and the UniProt subcellular-location keyword. Reason: ER membrane is the established primary location of HMGCR; the electronic mapping is correct and redundant with the experimental annotations. Supporting Evidence: file:human/HMGCR/HMGCR-uniprot.txt Endoplasmic reticulum membrane
GO:0008299 isoprenoid biosynthetic process	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO electronic mapping to isoprenoid biosynthesis from the HMG-CoA reductase domains. Correct pathway context for the mevalonate-producing step. Reason: Correct: HMGCR produces mevalonate, the precursor of all isoprenoids. Redundant with the IBA annotation to the same term. Supporting Evidence: PMID:10698924 the committed step in the biosynthesis of sterols and isoprenoids
GO:0015936 coenzyme A metabolic process	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: InterPro2GO electronic mapping to coenzyme A metabolic process, triggered by the CoA-binding/substrate-binding domains. HMGCR uses HMG-CoA as substrate and releases CoA, but it is not a component of a coenzyme A metabolic pathway. Reason: Over-annotation from a domain-to-GO rule. CoA is released as a product of the HMGCR reaction (its acyl-CoA substrate is reduced), but HMGCR does not participate in coenzyme A biosynthesis or turnover as a metabolic process. The molecular-level CoA involvement is more precisely captured by the coenzyme A binding (GO:0120225) annotation. Supporting Evidence: file:human/HMGCR/HMGCR-uniprot.txt the rate-limiting step in the synthesis of
GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: InterPro2GO electronic mapping to a general oxidoreductase parent term. HMGCR is an oxidoreductase acting with NADPH, but this term is far less specific than the exact activity GO:0004420. Reason: Grandparent of the precise, well-supported GO:0004420 hydroxymethylglutaryl-CoA reductase (NADPH) activity. It is not wrong but is uninformative given the specific term is annotated; treated as an over-general over-annotation rather than removed. Supporting Evidence: PMID:10698924 catalyzes the formation of
GO:0050661 NADP binding	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: InterPro2GO electronic mapping to NADP binding. HMGCR binds NADP(H) as its redox cofactor; a more specific NADPH binding (GO:0070402) annotation with direct structural evidence also exists. Reason: Correct at the cofactor level but redundant with and less specific than the structure-based GO:0070402 NADPH binding IDA. Kept as non-core supporting molecular detail rather than a core function. Supporting Evidence: file:human/HMGCR/HMGCR-uniprot.txt the rate-limiting step in the synthesis of
GO:0005515 protein binding	IPI PMID:23169578 The UBIAD1 prenyltransferase links menaquinone-4 [corrected]...	MARK AS OVER ANNOTATED	Summary: IPI protein-binding annotation supported by a physical interaction between HMGCR and the prenyltransferase UBIAD1 (yeast two-hybrid plus immunoprecipitation). The identifier is correct but the GO term is uninformative. Reason: Bare "protein binding" (GO:0005515) does not convey a specific molecular function. The underlying UBIAD1 interaction is real, but per curation guidelines this generic term is flagged as an over-annotation rather than a core function; it is not removed because the experimental interaction is genuine. Supporting Evidence: PMID:23169578 interacts with HMGCR and SOAT1, enzymes catalyzing cholesterol synthesis and PMID:23169578 using yeast two-hybrid screening and immunoprecipitation
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: IPI protein-binding annotation from a proteome-scale affinity-purification/mass spectrometry interactome study (BioPlex). Generic binding term with no specific molecular-function content. Reason: High-throughput AP-MS interaction; the "protein binding" (GO:0005515) term is uninformative about molecular function. Retained (not removed) as a genuine high-throughput interaction but flagged as over-annotated per curation guidelines. Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks.
GO:0042177 negative regulation of protein catabolic process	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Electronic transfer (Ensembl Compara) from the mouse ortholog (Q01237) of a role in negatively regulating protein catabolism. This is an indirect, downstream consequence of mevalonate-pathway output rather than a direct HMGCR function. Reason: Not a direct molecular activity or process of HMGCR; it is an orthology-transferred regulatory effect several steps removed from the enzyme's catalytic role. Treated as an over-annotation rather than removed, since it is an electronic ortholog transfer that may reflect a real but indirect pleiotropic effect. Supporting Evidence: file:human/HMGCR/HMGCR-uniprot.txt the rate-limiting step in the synthesis of
GO:0050709 negative regulation of protein secretion	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Electronic transfer (Ensembl Compara) from the mouse ortholog (Q01237) of a role in negatively regulating protein secretion. Indirect downstream effect, not a direct HMGCR function. Reason: As with the protein-catabolism annotation, this is an orthology-transferred, indirect regulatory role rather than the enzyme's core function. Flagged as over-annotated. Supporting Evidence: file:human/HMGCR/HMGCR-uniprot.txt the rate-limiting step in the synthesis of
GO:1900222 negative regulation of amyloid-beta clearance	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Electronic transfer (Ensembl Compara) from the mouse ortholog (Q01237) of a role in negatively regulating amyloid-beta clearance. A highly indirect, tissue/context dependent effect linked to cholesterol metabolism, not a direct HMGCR function. Reason: Very indirect, downstream neurobiological effect transferred by orthology; far removed from HMGCR's catalytic role in the mevalonate pathway. Flagged as over-annotated rather than removed given it is an electronic ortholog transfer. Supporting Evidence: file:human/HMGCR/HMGCR-uniprot.txt the rate-limiting step in the synthesis of
GO:0005789 endoplasmic reticulum membrane	IPI PMID:10698924 Crystal structure of the catalytic portion of human HMG-CoA ...	ACCEPT	Summary: ComplexPortal-assigned ER membrane location for HMGCR. Consistent with the enzyme being a polytopic ER membrane protein whose catalytic domain projects into the cytosol. Reason: ER membrane is the primary, well-established location of HMGCR; corroborated by experimental subcellular-location and topology data. Supporting Evidence: file:human/HMGCR/HMGCR-uniprot.txt Endoplasmic reticulum membrane
GO:0006695 cholesterol biosynthetic process	IDA PMID:23063590 Artemisinic acid inhibits melanogenesis through downregulati...	ACCEPT	Summary: Direct assignment of HMGCR to cholesterol biosynthesis. HMGCR catalyzes the rate-limiting mevalonate-producing step of cholesterol synthesis; the cited study links HMGCR-dependent cholesterol synthesis to melanogenesis. Reason: Correct and central: cholesterol biosynthesis is the best-known role of the mevalonate pathway, and HMGCR is its rate-limiting step. This is a core biological process for the gene. Supporting Evidence: PMID:21357570 is the rate-controlling enzyme of PMID:36745799 facilitates the rate-limiting step in cholesterol synthesis
GO:0008299 isoprenoid biosynthetic process	NAS PMID:18540668 Thermodynamic and structure guided design of statin based in...	ACCEPT	Summary: Non-traceable author-statement assignment of HMGCR to isoprenoid biosynthesis, from a statin-inhibitor structure/design paper that treats HMGCR as the mevalonate-pathway enzyme. Reason: Correct pathway assignment; HMGCR produces mevalonate for isoprenoid biosynthesis. Redundant with the IBA/IEA annotations to the same term. Supporting Evidence: PMID:18540668 statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) inhibitors
GO:0004420 hydroxymethylglutaryl-CoA reductase (NADPH) activity	EXP PMID:36745799 Limb girdle muscular disease caused by HMGCR mutation and st...	ACCEPT	Summary: Experimental demonstration of HMGCR catalytic activity in the context of an LGMDR28 disease variant, with kinetic characterization (KM for HMG-CoA) and statin (pravastatin) inhibition; disease rescued by mevalonolactone. Reason: Direct experimental support for the core catalytic activity in human HMGCR; strong evidence anchoring GO:0004420 as the core molecular function. Supporting Evidence: PMID:36745799 facilitates the rate-limiting step in cholesterol synthesis
GO:0004420 hydroxymethylglutaryl-CoA reductase (NADPH) activity	EXP PMID:6995544 Multivalent feedback regulation of HMG CoA reductase, a cont...	ACCEPT	Summary: Experimental study of HMGCR as the mevalonate-synthesizing enzyme subject to multivalent feedback regulation, using the competitive inhibitor compactin. Reason: Classic experimental characterization of the enzyme that synthesizes mevalonate; supports the core catalytic activity and its feedback regulation. Supporting Evidence: PMID:6995544 the enzyme that synthesizes mevalonate
GO:0005789 endoplasmic reticulum membrane	EXP PMID:17180682 Localization of the pre-squalene segment of the isoprenoid b...	ACCEPT	Summary: Experimental subcellular-localization study assigning HMGCR (and the pre-squalene isoprenoid segment) to the ER membrane (and peroxisomes). Reason: ER membrane is the primary, functionally central location of HMGCR; experimentally supported. Supporting Evidence: file:human/HMGCR/HMGCR-uniprot.txt Endoplasmic reticulum membrane
GO:0042177 negative regulation of protein catabolic process	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: Sequence-similarity transfer (from mouse Q01237) of a role in negatively regulating protein catabolism. Same indirect, non-core role as the corresponding IEA annotation. Reason: Indirect, ortholog-transferred regulatory role that is several steps removed from HMGCR's catalytic function; not a core process. Flagged as over-annotated. Supporting Evidence: file:human/HMGCR/HMGCR-uniprot.txt the rate-limiting step in the synthesis of
GO:0050709 negative regulation of protein secretion	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: Sequence-similarity transfer (from mouse Q01237) of a role in negatively regulating protein secretion. Indirect, non-core role. Reason: Ortholog-transferred, indirect regulatory effect rather than a direct HMGCR function. Flagged as over-annotated. Supporting Evidence: file:human/HMGCR/HMGCR-uniprot.txt the rate-limiting step in the synthesis of
GO:0120225 coenzyme A binding	IDA PMID:10698924 Crystal structure of the catalytic portion of human HMG-CoA ...	ACCEPT	Summary: Direct structural demonstration that HMGCR binds coenzyme A, from crystal structures of the catalytic domain in complex with HMG-CoA and with HMG + CoA. Reason: Supported by co-crystal structures; a genuine molecular-function detail of the enzyme's HMG-CoA substrate/CoA interaction. Kept as a supporting (non-primary) molecular function underlying catalysis. Supporting Evidence: PMID:10698924 with HMG and CoA, and with HMG, CoA and NADP(+)
GO:0004420 hydroxymethylglutaryl-CoA reductase (NADPH) activity	IDA PMID:21357570 Epigallocatechin-3-gallate potently inhibits the in vitro ac...	ACCEPT	Summary: Direct in vitro measurement of human HMGCR enzymatic activity (rate-controlling enzyme of cholesterol synthesis) in a kinetic/inhibition study with EGCG. Reason: Direct experimental support for the core catalytic activity of HMGCR. Supporting Evidence: PMID:21357570 is the rate-controlling enzyme of
GO:1900222 negative regulation of amyloid-beta clearance	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: Sequence-similarity transfer (from mouse Q01237) of a role in negatively regulating amyloid-beta clearance. Highly indirect, context-dependent effect. Reason: Very indirect, downstream neurobiological role transferred by orthology; not a core HMGCR function. Flagged as over-annotated. Supporting Evidence: file:human/HMGCR/HMGCR-uniprot.txt the rate-limiting step in the synthesis of
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-9621410	ACCEPT	Summary: Reactome traceable assignment of HMGCR to the ER membrane (HMGCR gene expression pathway context). Reason: Consistent with the established ER membrane localization of HMGCR. Supporting Evidence: file:human/HMGCR/HMGCR-uniprot.txt Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-1655826	ACCEPT	Summary: Reactome traceable assignment of HMGCR to the ER membrane (HMGCR expression pathway context). Reason: Consistent with the established ER membrane localization of HMGCR. Supporting Evidence: file:human/HMGCR/HMGCR-uniprot.txt Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-191352	ACCEPT	Summary: Reactome traceable assignment of HMGCR to the ER membrane in the reaction "HMGCR dimer reduces bHMG-CoA to MVA", the catalytic step of the mevalonate pathway. Reason: Consistent with the established ER membrane localization of the catalytically active HMGCR dimer. Supporting Evidence: file:human/HMGCR/HMGCR-uniprot.txt Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-9705584	ACCEPT	Summary: Reactome traceable assignment of HMGCR to the ER membrane in the reaction "HMGCR dimer binds statins". Reason: Consistent with the established ER membrane localization of HMGCR. Supporting Evidence: file:human/HMGCR/HMGCR-uniprot.txt Endoplasmic reticulum membrane
GO:0004420 hydroxymethylglutaryl-CoA reductase (NADPH) activity	IDA PMID:2991281 Human 3-hydroxy-3-methylglutaryl coenzyme A reductase. Conse...	ACCEPT	Summary: Direct characterization of human HMGCR (isolation and analysis of the full-length cDNA encoding the membrane-bound glycoprotein that regulates cholesterol synthesis), defining the catalytic C-terminal domain. Reason: Foundational human evidence for the enzyme's catalytic function and its two-domain architecture (membrane + catalytic). Supports GO:0004420 as core. Supporting Evidence: PMID:2991281 the membrane-bound glycoprotein that regulates cholesterol synthesis
GO:0005778 peroxisomal membrane	IDA PMID:17180682 Localization of the pre-squalene segment of the isoprenoid b...	KEEP AS NON CORE	Summary: Experimental (immunofluorescence/isotopic) evidence localizing the pre-squalene isoprenoid segment, including HMGCR, to peroxisomes in human cells. Reason: This is an experimental annotation and is retained. However, peroxisomal localization of the pre-squalene cholesterol-biosynthetic enzymes is contested in the literature and is secondary to the dominant ER membrane pool that mediates HMGCR's regulated activity. Marked non-core rather than accepted as a primary site. Supporting Evidence: PMID:17180682 isoprenoid/cholesterol biosynthetic pathway occur in peroxisomes
GO:0005783 endoplasmic reticulum	IDA PMID:17180682 Localization of the pre-squalene segment of the isoprenoid b...	ACCEPT	Summary: Experimental localization of HMGCR to the endoplasmic reticulum (parent compartment of the ER membrane where the protein resides). Reason: Correct; ER is the primary compartment of HMGCR. The more specific ER membrane annotation is preferred for the location detail, but the ER assignment is accurate. Supporting Evidence: file:human/HMGCR/HMGCR-uniprot.txt Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane	TAS PMID:2991281 Human 3-hydroxy-3-methylglutaryl coenzyme A reductase. Conse...	ACCEPT	Summary: Traceable author statement placing HMGCR in the ER membrane, based on the N-terminal membrane domain predicted to span the ER membrane multiple times. Reason: Consistent with the multi-pass ER membrane topology; ER membrane is the primary HMGCR location. Supporting Evidence: PMID:2991281 which is predicted to span
GO:0070402 NADPH binding	IDA PMID:10698924 Crystal structure of the catalytic portion of human HMG-CoA ...	ACCEPT	Summary: Direct structural demonstration that HMGCR binds NADP(H), from crystal structures of the catalytic domain in complex with HMG, CoA and NADP(+). Reason: Supported by co-crystal structures; NADPH is the obligate cofactor of the reduction reaction. Kept as a supporting molecular function underlying catalysis; more specific than the IEA NADP binding annotation. Supporting Evidence: PMID:10698924 with HMG, CoA and NADP(+)

Gene Description

Existing Annotations Review

Core Functions

NADPH-dependent reduction of (3S)-3-hydroxy-3-methylglutaryl-CoA to (R)-mevalonate and CoA, the rate-limiting and committed step of the mevalonate pathway, performed by the cytosolic catalytic domain of HMGCR (assembled as homodimers/homotetramers) at the endoplasmic reticulum membrane.

Production of mevalonate as the precursor for non-sterol isoprenoids (dolichol, ubiquinone, and farnesyl/geranylgeranyl prenyl groups), placing HMGCR at the head of isoprenoid biosynthesis in addition to cholesterol/sterol synthesis.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

📄 View Raw YAML