id: P04035
gene_symbol: HMGCR
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  HMGCR encodes 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase;
  EC 1.1.1.34), the rate-limiting and committed enzyme of the mevalonate pathway.
  It catalyzes the NADPH-dependent reduction of (3S)-3-hydroxy-3-methylglutaryl-CoA
  (HMG-CoA) to (R)-mevalonate and CoA, a two-step, four-electron reaction consuming
  two molecules of NADPH. Mevalonate is the precursor for cholesterol, dolichol,
  ubiquinone and the prenyl groups (farnesyl/geranylgeranyl) used in protein
  prenylation, so HMGCR sits at the head of sterol and non-sterol isoprenoid
  biosynthesis. HMGCR is a polytopic (multi-pass) endoplasmic reticulum membrane
  protein of 888 residues: its N-terminal membrane-anchored region contains a
  sterol-sensing domain that, together with INSIG proteins and SREBP/SCAP, mediates
  sterol-accelerated ubiquitination and ER-associated degradation and feedback
  regulation of the enzyme, while the C-terminal cytosolic domain is catalytic and
  assembles into homodimers/homotetramers. HMGCR is the molecular target of the
  statin class of cholesterol-lowering drugs, which act as competitive inhibitors
  at the HMG-CoA/cofactor site. Bi-allelic loss-of-function HMGCR variants cause an
  autosomal-recessive limb-girdle muscular dystrophy (LGMDR28).
alternative_products:
- name: 1 (HMGCR-1a {ECO:0000303|PubMed:22989091})
  id: P04035-1
- name: 2 (HMGCR-1c {ECO:0000303|PubMed:22989091})
  id: P04035-2
  sequence_note: VSP_002207
- name: 3 (HMGCR-1b {ECO:0000303|PubMed:22989091})
  id: P04035-3
  sequence_note: VSP_046492
existing_annotations:
- term:
    id: GO:0004420
    label: hydroxymethylglutaryl-CoA reductase (NADPH) activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Correct and specific. HMGCR is the rate-limiting enzyme of the mevalonate
      pathway; the IBA is corroborated by human experimental evidence.
    supported_by:
    - reference_id: PMID:10698924
      supporting_text: >-
        catalyzes the formation of
    - reference_id: PMID:10698924
      supporting_text: >-
        mevalonate, the committed step
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:2991281
      supporting_text: >-
        the membrane-bound glycoprotein that regulates cholesterol synthesis
    - reference_id: file:human/HMGCR/HMGCR-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0016126
    label: sterol biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic assignment of HMGCR to sterol biosynthesis. As the rate-limiting
      step producing mevalonate, HMGCR is required for cholesterol/sterol synthesis.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:10698924
      supporting_text: >-
        the committed step in the biosynthesis of sterols and isoprenoids
- term:
    id: GO:0008299
    label: isoprenoid biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: >-
      Correct: HMGCR is the committed step producing mevalonate for both sterol and
      non-sterol isoprenoid branches.
    supported_by:
    - reference_id: PMID:10698924
      supporting_text: >-
        the committed step in the biosynthesis of sterols and isoprenoids
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:17180682
      supporting_text: >-
        isoprenoid/cholesterol biosynthetic pathway occur in peroxisomes
- term:
    id: GO:0004420
    label: hydroxymethylglutaryl-CoA reductase (NADPH) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic (InterPro/EC/RHEA-based) assignment of the core catalytic activity.
      Redundant with the experimental and IBA annotations to the same term.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/HMGCR/HMGCR-uniprot.txt
      supporting_text: the rate-limiting step in the synthesis of
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt Subcellular-Location keyword mapping to peroxisomal membrane, reflecting
      the reported (contested) peroxisomal pool of pre-squalene isoprenoid enzymes.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/HMGCR/HMGCR-uniprot.txt
      supporting_text: Peroxisome membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Electronic assignment of the primary ER membrane location, mapped from InterPro
      (metazoan HMGCR) and the UniProt subcellular-location keyword.
    action: ACCEPT
    reason: >-
      ER membrane is the established primary location of HMGCR; the electronic mapping
      is correct and redundant with the experimental annotations.
    supported_by:
    - reference_id: file:human/HMGCR/HMGCR-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0008299
    label: isoprenoid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO electronic mapping to isoprenoid biosynthesis from the HMG-CoA
      reductase domains. Correct pathway context for the mevalonate-producing step.
    action: ACCEPT
    reason: >-
      Correct: HMGCR produces mevalonate, the precursor of all isoprenoids. Redundant
      with the IBA annotation to the same term.
    supported_by:
    - reference_id: PMID:10698924
      supporting_text: >-
        the committed step in the biosynthesis of sterols and isoprenoids
- term:
    id: GO:0015936
    label: coenzyme A metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/HMGCR/HMGCR-uniprot.txt
      supporting_text: the rate-limiting step in the synthesis of
- term:
    id: GO:0016616
    label: oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP
      as acceptor
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:10698924
      supporting_text: >-
        catalyzes the formation of
- term:
    id: GO:0050661
    label: NADP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/HMGCR/HMGCR-uniprot.txt
      supporting_text: the rate-limiting step in the synthesis of
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23169578
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:23169578
      supporting_text: >-
        interacts with HMGCR and SOAT1, enzymes catalyzing cholesterol synthesis and
    - reference_id: PMID:23169578
      supporting_text: using yeast two-hybrid screening and immunoprecipitation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: >-
        Through affinity-purification mass spectrometry, we have created two
        proteome-scale, cell-line-specific interaction networks.
- term:
    id: GO:0042177
    label: negative regulation of protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/HMGCR/HMGCR-uniprot.txt
      supporting_text: the rate-limiting step in the synthesis of
- term:
    id: GO:0050709
    label: negative regulation of protein secretion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/HMGCR/HMGCR-uniprot.txt
      supporting_text: the rate-limiting step in the synthesis of
- term:
    id: GO:1900222
    label: negative regulation of amyloid-beta clearance
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/HMGCR/HMGCR-uniprot.txt
      supporting_text: the rate-limiting step in the synthesis of
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IPI
  original_reference_id: PMID:10698924
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: >-
      ER membrane is the primary, well-established location of HMGCR; corroborated by
      experimental subcellular-location and topology data.
    supported_by:
    - reference_id: file:human/HMGCR/HMGCR-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:23063590
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:21357570
      supporting_text: >-
        is the rate-controlling enzyme of
    - reference_id: PMID:36745799
      supporting_text: >-
        facilitates the rate-limiting step in cholesterol synthesis
- term:
    id: GO:0008299
    label: isoprenoid biosynthetic process
  evidence_type: NAS
  original_reference_id: PMID:18540668
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: >-
      Correct pathway assignment; HMGCR produces mevalonate for isoprenoid biosynthesis.
      Redundant with the IBA/IEA annotations to the same term.
    supported_by:
    - reference_id: PMID:18540668
      supporting_text: >-
        statins, 3-hydroxy-3-methylglutaryl
        coenzyme A reductase (HMGR) inhibitors
- term:
    id: GO:0004420
    label: hydroxymethylglutaryl-CoA reductase (NADPH) activity
  evidence_type: EXP
  original_reference_id: PMID:36745799
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Direct experimental support for the core catalytic activity in human HMGCR;
      strong evidence anchoring GO:0004420 as the core molecular function.
    supported_by:
    - reference_id: PMID:36745799
      supporting_text: >-
        facilitates the rate-limiting step in cholesterol synthesis
- term:
    id: GO:0004420
    label: hydroxymethylglutaryl-CoA reductase (NADPH) activity
  evidence_type: EXP
  original_reference_id: PMID:6995544
  qualifier: enables
  review:
    summary: >-
      Experimental study of HMGCR as the mevalonate-synthesizing enzyme subject to
      multivalent feedback regulation, using the competitive inhibitor compactin.
    action: ACCEPT
    reason: >-
      Classic experimental characterization of the enzyme that synthesizes mevalonate;
      supports the core catalytic activity and its feedback regulation.
    supported_by:
    - reference_id: PMID:6995544
      supporting_text: >-
        the enzyme that synthesizes mevalonate
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:17180682
  qualifier: located_in
  review:
    summary: >-
      Experimental subcellular-localization study assigning HMGCR (and the pre-squalene
      isoprenoid segment) to the ER membrane (and peroxisomes).
    action: ACCEPT
    reason: >-
      ER membrane is the primary, functionally central location of HMGCR; experimentally
      supported.
    supported_by:
    - reference_id: file:human/HMGCR/HMGCR-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0042177
    label: negative regulation of protein catabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Indirect, ortholog-transferred regulatory role that is several steps removed from
      HMGCR's catalytic function; not a core process. Flagged as over-annotated.
    supported_by:
    - reference_id: file:human/HMGCR/HMGCR-uniprot.txt
      supporting_text: the rate-limiting step in the synthesis of
- term:
    id: GO:0050709
    label: negative regulation of protein secretion
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence-similarity transfer (from mouse Q01237) of a role in negatively
      regulating protein secretion. Indirect, non-core role.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Ortholog-transferred, indirect regulatory effect rather than a direct HMGCR
      function. Flagged as over-annotated.
    supported_by:
    - reference_id: file:human/HMGCR/HMGCR-uniprot.txt
      supporting_text: the rate-limiting step in the synthesis of
- term:
    id: GO:0120225
    label: coenzyme A binding
  evidence_type: IDA
  original_reference_id: PMID:10698924
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:10698924
      supporting_text: >-
        with HMG and CoA, and with HMG, CoA and NADP(+)
- term:
    id: GO:0004420
    label: hydroxymethylglutaryl-CoA reductase (NADPH) activity
  evidence_type: IDA
  original_reference_id: PMID:21357570
  qualifier: enables
  review:
    summary: >-
      Direct in vitro measurement of human HMGCR enzymatic activity (rate-controlling
      enzyme of cholesterol synthesis) in a kinetic/inhibition study with EGCG.
    action: ACCEPT
    reason: >-
      Direct experimental support for the core catalytic activity of HMGCR.
    supported_by:
    - reference_id: PMID:21357570
      supporting_text: >-
        is the rate-controlling enzyme of
- term:
    id: GO:1900222
    label: negative regulation of amyloid-beta clearance
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence-similarity transfer (from mouse Q01237) of a role in negatively
      regulating amyloid-beta clearance. Highly indirect, context-dependent effect.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Very indirect, downstream neurobiological role transferred by orthology; not a
      core HMGCR function. Flagged as over-annotated.
    supported_by:
    - reference_id: file:human/HMGCR/HMGCR-uniprot.txt
      supporting_text: the rate-limiting step in the synthesis of
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9621410
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable assignment of HMGCR to the ER membrane (HMGCR gene expression
      pathway context).
    action: ACCEPT
    reason: >-
      Consistent with the established ER membrane localization of HMGCR.
    supported_by:
    - reference_id: file:human/HMGCR/HMGCR-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1655826
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable assignment of HMGCR to the ER membrane (HMGCR expression
      pathway context).
    action: ACCEPT
    reason: >-
      Consistent with the established ER membrane localization of HMGCR.
    supported_by:
    - reference_id: file:human/HMGCR/HMGCR-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-191352
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: >-
      Consistent with the established ER membrane localization of the catalytically
      active HMGCR dimer.
    supported_by:
    - reference_id: file:human/HMGCR/HMGCR-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9705584
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable assignment of HMGCR to the ER membrane in the reaction
      "HMGCR dimer binds statins".
    action: ACCEPT
    reason: >-
      Consistent with the established ER membrane localization of HMGCR.
    supported_by:
    - reference_id: file:human/HMGCR/HMGCR-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0004420
    label: hydroxymethylglutaryl-CoA reductase (NADPH) activity
  evidence_type: IDA
  original_reference_id: PMID:2991281
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Foundational human evidence for the enzyme's catalytic function and its two-domain
      architecture (membrane + catalytic). Supports GO:0004420 as core.
    supported_by:
    - reference_id: PMID:2991281
      supporting_text: >-
        the membrane-bound glycoprotein that regulates cholesterol synthesis
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:17180682
  qualifier: located_in
  review:
    summary: >-
      Experimental (immunofluorescence/isotopic) evidence localizing the pre-squalene
      isoprenoid segment, including HMGCR, to peroxisomes in human cells.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:17180682
      supporting_text: >-
        isoprenoid/cholesterol biosynthetic pathway occur in peroxisomes
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:17180682
  qualifier: located_in
  review:
    summary: >-
      Experimental localization of HMGCR to the endoplasmic reticulum (parent compartment
      of the ER membrane where the protein resides).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/HMGCR/HMGCR-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: PMID:2991281
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: >-
      Consistent with the multi-pass ER membrane topology; ER membrane is the primary
      HMGCR location.
    supported_by:
    - reference_id: PMID:2991281
      supporting_text: >-
        which is predicted to span
- term:
    id: GO:0070402
    label: NADPH binding
  evidence_type: IDA
  original_reference_id: PMID:10698924
  qualifier: enables
  review:
    summary: >-
      Direct structural demonstration that HMGCR binds NADP(H), from crystal structures
      of the catalytic domain in complex with HMG, CoA and NADP(+).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:10698924
      supporting_text: >-
        with HMG, CoA and NADP(+)
core_functions:
- description: >-
    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.
  molecular_function:
    id: GO:0004420
    label: hydroxymethylglutaryl-CoA reductase (NADPH) activity
  directly_involved_in:
  - id: GO:0006695
    label: cholesterol biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:10698924
    supporting_text: >-
      the committed step in the biosynthesis of sterols and isoprenoids
  - reference_id: PMID:36745799
    supporting_text: >-
      facilitates the rate-limiting step in cholesterol synthesis
- description: >-
    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.
  molecular_function:
    id: GO:0004420
    label: hydroxymethylglutaryl-CoA reductase (NADPH) activity
  directly_involved_in:
  - id: GO:0008299
    label: isoprenoid biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:10698924
    supporting_text: >-
      the committed step in the biosynthesis of sterols and isoprenoids
proposed_new_terms: []
suggested_questions:
- question: >-
    Is the reported peroxisomal pool of HMGCR functionally significant, or is HMGCR
    activity essentially entirely ER-membrane-based in human cells?
- question: >-
    To what extent do the orthology-transferred regulatory roles (negative regulation
    of protein secretion/catabolism, amyloid-beta clearance) reflect direct HMGCR
    effects versus indirect consequences of altered cholesterol/isoprenoid levels?
suggested_experiments:
- description: >-
    Quantify the relative contribution of ER versus peroxisomal HMGCR to cellular
    mevalonate/cholesterol synthesis using compartment-targeted assays or organelle
    fractionation combined with isotopic flux analysis.
- description: >-
    Structurally and enzymatically characterize LGMDR28 disease variants to relate
    catalytic/thermal-stability defects to muscle phenotype and mevalonolactone rescue.
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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/HMGCR/HMGCR-uniprot.txt
  title: UniProtKB entry P04035 (HMDH_HUMAN), 3-hydroxy-3-methylglutaryl-coenzyme A reductase
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Curated UniProt record for HMGCR; source of catalytic-activity, subcellular
      location and topology statements used as file: supporting text.
- id: PMID:10698924
  title: 'Crystal structure of the catalytic portion of human HMG-CoA reductase: insights
    into regulation of activity and catalysis.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Human catalytic-domain crystal structures with HMG-CoA, CoA and NADP(+); defines
      catalysis, cofactor/CoA binding and homotetramer/homodimer state. Supports
      GO:0004420, GO:0120225, GO:0070402.
- id: PMID:17180682
  title: Localization of the pre-squalene segment of the isoprenoid biosynthetic pathway
    in mammalian peroxisomes.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Supports ER and peroxisomal localization of pre-squalene isoprenoid enzymes;
      peroxisomal claim is contested, so treated as non-core for HMGCR.
- id: PMID:18540668
  title: Thermodynamic and structure guided design of statin based inhibitors of 3-hydroxy-3-methylglutaryl
    coenzyme A reductase.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Statin-inhibitor structure/design paper; treats HMGCR as the mevalonate-pathway
      target enzyme. Basis for the NAS isoprenoid-biosynthesis annotation.
- id: PMID:21357570
  title: Epigallocatechin-3-gallate potently inhibits the in vitro activity of hydroxy-3-methyl-glutaryl-CoA
    reductase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Direct in vitro human HMGCR activity measurement (rate-controlling enzyme of
      cholesterol synthesis). Supports GO:0004420.
- id: PMID:23063590
  title: Artemisinic acid inhibits melanogenesis through downregulation of C/EBP α-dependent
    expression of HMG-CoA reductase gene.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Links HMGCR-dependent cholesterol synthesis to melanogenesis via downregulation
      of HMGCR expression; basis of the cholesterol-biosynthetic-process IDA. The
      cholesterol-biosynthesis role itself is independently well established.
- id: PMID:23169578
  title: The UBIAD1 prenyltransferase links menaquinone-4 [corrected] synthesis to
    cholesterol metabolic enzymes.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Reports a physical HMGCR-UBIAD1 interaction (Y2H + IP); basis of a protein binding
      IPI, flagged as over-annotated because the GO term is uninformative.
- id: PMID:2991281
  title: Human 3-hydroxy-3-methylglutaryl coenzyme A reductase. Conserved domains
    responsible for catalytic activity and sterol-regulated degradation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Human full-length cDNA; defines catalytic C-terminal domain and sterol-regulated
      membrane domain / ER membrane topology. Supports GO:0004420 and ER membrane.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Proteome-scale AP-MS interactome (BioPlex); source of a generic protein binding
      IPI, flagged as over-annotated.
- id: PMID:36745799
  title: Limb girdle muscular disease caused by HMGCR mutation and statin myopathy
    treatable with mevalonolactone.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Experimental catalytic characterization of human HMGCR and an LGMDR28 variant,
      kinetics, statin inhibition, and disease context. Supports GO:0004420 and the
      rate-limiting cholesterol-synthesis role.
- id: PMID:6995544
  title: Multivalent feedback regulation of HMG CoA reductase, a control mechanism
    coordinating isoprenoid synthesis and cell growth.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Classic study of HMGCR as the mevalonate-synthesizing enzyme under multivalent
      feedback regulation. Supports GO:0004420 and pathway/regulatory context.
- id: Reactome:R-HSA-1655826
  title: Expression of 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase (HMGCR)
  findings: []
- id: Reactome:R-HSA-191352
  title: HMGCR dimer reduces bHMG-CoA to MVA
  findings: []
- id: Reactome:R-HSA-9621410
  title: HMGCR gene expression
  findings: []
- id: Reactome:R-HSA-9705584
  title: HMGCR dimer binds statins
  findings: []