id: Q01581
gene_symbol: HMGCS1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  HMGCS1 is the cytoplasmic (cytosolic) isoform of hydroxymethylglutaryl-CoA
  synthase (HMG-CoA synthase; EC 2.3.3.10). It catalyzes the condensation of
  acetyl-CoA with acetoacetyl-CoA (with water) to form (3S)-3-hydroxy-3-
  methylglutaryl-CoA (HMG-CoA) plus CoA, the first committed step of the
  cytosolic mevalonate pathway. The HMG-CoA it produces is reduced by HMG-CoA
  reductase (HMGCR) to mevalonate, the precursor of isoprenoids and cholesterol;
  HMGCS1 thus feeds isoprenoid and cholesterol biosynthesis. The enzyme is a
  homodimer with a thiolase-like fold and uses an active-site cysteine (Cys129)
  that forms an acetyl-thioester intermediate during catalysis. It is a soluble
  cytosolic protein and is distinct from the mitochondrial isoform HMGCS2, which
  produces HMG-CoA for ketone-body synthesis (ketogenesis). HMGCS1 is a
  sterol-regulatory-element-binding-protein (SREBP)-regulated cholesterogenic
  gene, and biallelic loss-of-function variants cause a congenital rigid-spine
  myopathy.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:20346956
  title: Crystal structures of human HMG-CoA synthase isoforms provide insights into
    inherited ketogenesis disorders and inhibitor design.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Solved the crystal structures of both human HMGCS isoforms (hHMGCS1 cytosolic,
      hHMGCS2 mitochondrial; PDB 2P8U for HMGCS1), establishing the homodimer and
      distinguishing the cytosolic/cholesterol from the mitochondrial/ketogenesis
      isoform. Directly supports the homodimerization and catalytic-function claims.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale BioPlex 2.0 AP-MS interactome screen; HMGCS1 appears only as an
      IntAct/BioPlex bait/prey (interactor SLC22A5). Correctly cited for a physical
      interaction but uninformative about molecular function.
- 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: >-
      Large-scale BioPlex 3.0 AP-MS interactome screen; same class of evidence as
      PMID:28514442. Supports only a bare protein-binding IPI, not a specific function.
- id: PMID:7911016
  title: Molecular cloning and nucleotide sequence of complementary DNA for human
    hepatic cytosolic acetoacetyl-coenzyme A thiolase.
  findings: []
  reference_review:
    relevance: LOW
    correctness: MISCITED
    review_notes: >-
      This paper is about cytosolic acetoacetyl-CoA thiolase (ACAT2), the enzyme
      immediately UPSTREAM of HMGCS1 in the mevalonate pathway, not about HMGCS1
      itself. It is used only as the reference for a curator IC (inferred from
      GO:0004421) placing HMGCS1 in cholesterol biosynthesis. The conclusion (HMGCS1
      acts in cholesterol biosynthesis) is correct, but the reference is not about
      this gene.
- id: PMID:7913309
  title: 'Human cytoplasmic 3-hydroxy-3-methylglutaryl coenzyme A synthase: expression,
    purification, and characterization of recombinant wild-type and Cys129 mutant
    enzymes.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Expression, purification and kinetic characterization of recombinant human
      cytoplasmic HMG-CoA synthase, and demonstration that the active-site Cys129 is
      required for catalysis. Directly establishes HMGCS1 catalytic activity.
- id: Reactome:R-HSA-1655848
  title: Expression of Hydroxymethylglutaryl coenzyme A synthase (HMGCS1)
  findings: []
- id: Reactome:R-HSA-191323
  title: HMGCS1 condenses Ac-CoA and ACA-CoA to form bHMG-CoA
  findings: []
- id: Reactome:R-HSA-9969896
  title: Lanosterol biosynthesis
  findings: []
- id: file:human/HMGCS1/HMGCS1-uniprot.txt
  title: UniProtKB Q01581 (HMCS1_HUMAN) curated record
  findings: []
existing_annotations:
- term:
    id: GO:0004421
    label: hydroxymethylglutaryl-CoA synthase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Core molecular function. Phylogenetically inferred HMG-CoA synthase activity,
      the defining and experimentally established catalytic activity of HMGCS1.
    action: ACCEPT
    reason: >-
      This is the correct, specific molecular function of HMGCS1 and is well supported
      experimentally (kinetics and active-site mutagenesis). The IBA is consistent
      across the HMG-CoA synthase family.
    supported_by:
    - reference_id: PMID:7913309
      supporting_text: Mutation of Cys129 to serine or alanine destroys
    - reference_id: file:human/HMGCS1/HMGCS1-uniprot.txt
      supporting_text: Catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA
- term:
    id: GO:0006084
    label: acetyl-CoA metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Acetyl-CoA is a substrate of HMGCS1, so participation in acetyl-CoA metabolism
      is accurate but generic relative to the enzyme's committed role in the
      mevalonate/cholesterol pathway.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct and phylogenetically reviewed (IBA), but this is an upstream-substrate
      process term rather than the core function; the cholesterol/isoprenoid
      biosynthesis terms better capture the biological role. Retain as non-core.
    supported_by:
    - reference_id: file:human/HMGCS1/HMGCS1-uniprot.txt
      supporting_text: Catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA
- term:
    id: GO:0004421
    label: hydroxymethylglutaryl-CoA synthase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated (ARBA/InterPro/RHEA/EC) assignment of the same core HMG-CoA synthase
      activity; the mapping (EC 2.3.3.10, RHEA:10188) matches the experimentally
      established reaction.
    action: ACCEPT
    reason: >-
      Duplicate of the experimentally/phylogenetically supported core MF; the EC and
      RHEA mappings are exactly correct.
    supported_by:
    - reference_id: file:human/HMGCS1/HMGCS1-uniprot.txt
      supporting_text: EC=2.3.3.10
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Cytoplasmic localization from the UniProt subcellular-location vocabulary
      mapping, consistent with the curated location of this cytosolic enzyme.
    action: ACCEPT
    reason: >-
      HMGCS1 is a soluble cytosolic protein; cytoplasm is correct (the more specific
      cytosol term is also annotated).
    supported_by:
    - reference_id: file:human/HMGCS1/HMGCS1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0006084
    label: acetyl-CoA metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO assignment of acetyl-CoA metabolic process, duplicating the IBA of
      the same term.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate (acetyl-CoA is a substrate) but generic; keep as non-core, consistent
      with the IBA annotation of the same term.
    supported_by:
    - reference_id: file:human/HMGCS1/HMGCS1-uniprot.txt
      supporting_text: Catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA
- term:
    id: GO:0008299
    label: isoprenoid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      HMGCS1 catalyzes the first committed step of the mevalonate pathway, which
      supplies isoprenoid precursors; isoprenoid biosynthetic process is an accurate
      biological-process term for the enzyme.
    action: ACCEPT
    reason: >-
      The mevalonate pathway is the isoprenoid biosynthetic route in eukaryotes;
      HMGCS1's product HMG-CoA is the committed intermediate feeding it. This is a
      correct, appropriately general core process term.
    supported_by:
    - reference_id: Reactome:R-HSA-191323
      supporting_text: is involved in synthesis of isoprenoids and cholesterol biosynthesis
    - reference_id: file:human/HMGCS1/HMGCS1-uniprot.txt
      supporting_text: '(R)-mevalonate from acetyl-CoA: step 2/3.'
- term:
    id: GO:0016746
    label: acyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Very general acyltransferase (thiolase-like superfamily) activity term from
      InterPro; HMGCS1's actual transferase activity is the specific HMG-CoA synthase
      activity.
    action: MODIFY
    reason: >-
      GO:0016746 is a high-level parent of the specific, experimentally established
      HMG-CoA synthase activity. Replace with the specific molecular function
      GO:0004421.
    proposed_replacement_terms:
    - id: GO:0004421
      label: hydroxymethylglutaryl-CoA synthase activity
    supported_by:
    - reference_id: file:human/HMGCS1/HMGCS1-uniprot.txt
      supporting_text: EC=2.3.3.10
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: >-
      Bare protein-binding IPI from a large-scale BioPlex 2.0 AP-MS interactome screen
      (interactor SLC22A5). Not informative about HMGCS1 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation guidelines, uninformative bare protein binding is marked as
      over-annotated rather than retained as a core function; it does not identify a
      specific molecular activity. Not removed (it reflects a real experimentally
      detected interaction).
    supported_by:
    - reference_id: PMID:28514442
      supporting_text: BioPlex 2.0 constitutes a powerful resource for biological inquiry
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      Bare protein-binding IPI from a large-scale BioPlex 3.0 AP-MS interactome screen.
      Uninformative about HMGCS1 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Same class of high-throughput interaction evidence as PMID:28514442. Bare
      protein binding is over-annotated; kept (not removed) as it reflects a real
      detected interaction.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: These networks model the interactome whose
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9969896
  qualifier: involved_in
  review:
    summary: >-
      Core biological process. Via the mevalonate pathway, HMGCS1-produced HMG-CoA is
      the committed precursor of cholesterol; Reactome places HMGCS1 in cholesterol
      (lanosterol) biosynthesis.
    action: ACCEPT
    reason: >-
      Well-supported by the curated pathway and by UniProt (HMG-CoA is converted by
      HMGCR into mevalonate, a precursor for cholesterol synthesis). This is a central
      biological role of HMGCS1.
    supported_by:
    - reference_id: Reactome:R-HSA-9969896
      supporting_text: Cholesterol biosynthesis begins with the transformation of cytosolic
        acetyl CoA into lanosterol
    - reference_id: file:human/HMGCS1/HMGCS1-uniprot.txt
      supporting_text: mevalonate, a precursor for cholesterol synthesis.
- term:
    id: GO:0004421
    label: hydroxymethylglutaryl-CoA synthase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-191323
  qualifier: enables
  review:
    summary: >-
      Reactome traceable assertion of the core HMG-CoA synthase reaction (condensation
      of acetyl-CoA and acetoacetyl-CoA to HMG-CoA).
    action: ACCEPT
    reason: >-
      Duplicate of the core molecular function, supported by the curated Reactome
      reaction and by experimental characterization.
    supported_by:
    - reference_id: Reactome:R-HSA-191323
      supporting_text: catalyzes the condensation of acetyl CoA with acetoacetyl CoA
        to produce HMG-CoA
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Nucleoplasm localization from an HPA immunofluorescence dataset. HMGCS1 is a
      soluble cytosolic mevalonate-pathway enzyme, so nucleoplasm is not a core
      location.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Inconsistent with the well-established cytosolic role of the enzyme; likely
      reflects antibody staining that includes non-specific/soluble-pool signal. Kept
      (not removed) as it is an experimental IDA, but flagged as non-core over-
      annotation.
    supported_by:
    - reference_id: file:human/HMGCS1/HMGCS1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Cytosol localization from HPA immunofluorescence, matching the curated cytosolic
      location of this soluble enzyme.
    action: ACCEPT
    reason: >-
      Cytosol is the correct and most specific subcellular location for HMGCS1.
    supported_by:
    - reference_id: file:human/HMGCS1/HMGCS1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Plasma membrane localization from HPA immunofluorescence. HMGCS1 is a soluble
      cytosolic enzyme with no transmembrane region or membrane-anchoring feature, so
      plasma membrane is not a core location.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Inconsistent with the cytosolic biochemistry and structure of HMGCS1 (no TM
      segment; thiolase-like soluble fold); likely an HPA antibody artifact. Kept as
      an experimental IDA but flagged as over-annotation.
    supported_by:
    - reference_id: file:human/HMGCS1/HMGCS1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: IC
  original_reference_id: PMID:7911016
  qualifier: involved_in
  review:
    summary: >-
      Curator-inferred (IC, from GO:0004421) participation in cholesterol biosynthesis.
      The conclusion is correct for HMGCS1, though the cited reference (PMID:7911016)
      is about the upstream enzyme cytosolic acetoacetyl-CoA thiolase, not HMGCS1.
    action: ACCEPT
    reason: >-
      The cholesterol biosynthetic process assignment is a correct core role, inferred
      from the HMG-CoA synthase activity. The term is retained; the reference
      mismatch is recorded in reference_review for PMID:7911016.
    supported_by:
    - reference_id: file:human/HMGCS1/HMGCS1-uniprot.txt
      supporting_text: mevalonate, a precursor for cholesterol synthesis.
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:20346956
  qualifier: enables
  review:
    summary: >-
      HMGCS1 is a homodimer, established by the crystal structure of the human
      cytosolic isoform (PDB 2P8U).
    action: ACCEPT
    reason: >-
      Directly supported by the crystallographic and biochemical characterization
      showing HMGCS1 functions as a homodimer.
    supported_by:
    - reference_id: PMID:20346956
      supporting_text: we report high-resolution crystal structures of the human cytosolic
    - reference_id: file:human/HMGCS1/HMGCS1-uniprot.txt
      supporting_text: 'SUBUNIT: Homodimer.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1655848
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable assertion of cytosolic localization, consistent with the
      curated location.
    action: ACCEPT
    reason: >-
      Cytosol is the correct core location for this soluble mevalonate-pathway enzyme.
    supported_by:
    - reference_id: file:human/HMGCS1/HMGCS1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-191323
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable assertion of cytosolic localization (duplicate of the
      Reactome/HPA cytosol annotations).
    action: ACCEPT
    reason: >-
      Correct core location; consistent with the other cytosol annotations.
    supported_by:
    - reference_id: file:human/HMGCS1/HMGCS1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0006629
    label: lipid metabolic process
  evidence_type: NAS
  original_reference_id: PMID:7913309
  qualifier: involved_in
  review:
    summary: >-
      Very general lipid metabolic process assertion. HMGCS1's role is captured far
      more precisely by the cholesterol/isoprenoid biosynthetic process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0006629 is a broad ancestor of the specific mevalonate/cholesterol
      biosynthesis terms already annotated; it adds little and is an over-general
      (NAS) annotation. Not removed, but flagged as over-annotated.
    supported_by:
    - reference_id: file:human/HMGCS1/HMGCS1-uniprot.txt
      supporting_text: mevalonate, a precursor for cholesterol synthesis.
- term:
    id: GO:0004421
    label: hydroxymethylglutaryl-CoA synthase activity
  evidence_type: TAS
  original_reference_id: PMID:7913309
  qualifier: enables
  review:
    summary: >-
      Traceable assertion of HMG-CoA synthase activity from the biochemical
      characterization of recombinant human cytoplasmic HMGCS1.
    action: ACCEPT
    reason: >-
      Directly supported by expression/purification/kinetics and by Cys129 mutagenesis
      abolishing activity. This is the core molecular function.
    supported_by:
    - reference_id: PMID:7913309
      supporting_text: Mutation of Cys129 to serine or alanine destroys
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: TAS
  original_reference_id: PMID:7913309
  qualifier: located_in
  review:
    summary: >-
      Traceable assertion of cytoplasmic localization, consistent with the curated
      cytosolic location.
    action: ACCEPT
    reason: >-
      HMGCS1 is a cytoplasmic/cytosolic enzyme; correct localization.
    supported_by:
    - reference_id: file:human/HMGCS1/HMGCS1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
core_functions:
- description: >-
    Catalyzes the first committed step of the cytosolic mevalonate pathway:
    condensation of acetyl-CoA and acetoacetyl-CoA (with water) to form HMG-CoA
    plus CoA, feeding isoprenoid and cholesterol biosynthesis.
  molecular_function:
    id: GO:0004421
    label: hydroxymethylglutaryl-CoA synthase activity
  directly_involved_in:
  - id: GO:0006695
    label: cholesterol biosynthetic process
  - id: GO:0008299
    label: isoprenoid biosynthetic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/HMGCS1/HMGCS1-uniprot.txt
    supporting_text: Catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA
  - reference_id: PMID:7913309
    supporting_text: Mutation of Cys129 to serine or alanine destroys
  - reference_id: Reactome:R-HSA-191323
    supporting_text: is involved in synthesis of isoprenoids and cholesterol biosynthesis
proposed_new_terms: []
suggested_questions:
- question: >-
    Which non-catalytic protein interactions of HMGCS1 (e.g. with SLC22A5) are
    functionally meaningful, and does HMGCS1 have any moonlighting role beyond the
    mevalonate pathway?
- question: >-
    How do HMGCS1 loss-of-function variants cause a rigid-spine congenital myopathy
    despite the ubiquitous, essential nature of the mevalonate pathway, and why is
    the phenotype rescued by mevalonic acid?
suggested_experiments:
- description: >-
    Isoform-resolved subcellular fractionation plus validated-antibody
    immunofluorescence to test whether the HPA-reported nucleoplasm and plasma-
    membrane signals reflect genuine HMGCS1 pools or antibody artifacts.
- description: >-
    Metabolic flux analysis in HMGCS1-deficient patient muscle/cells to quantify the
    mevalonate/cholesterol-pathway defect and its rescue by exogenous mevalonate.