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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004421 hydroxymethylglutaryl-CoA synthase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function. Phylogenetically inferred HMG-CoA synthase activity, the defining and experimentally established catalytic activity of HMGCS1. 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. Supporting Evidence: PMID:7913309 Mutation of Cys129 to serine or alanine destroys file:human/HMGCS1/HMGCS1-uniprot.txt Catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA |
| GO:0006084 acetyl-CoA metabolic process | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/HMGCS1/HMGCS1-uniprot.txt Catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA |
| GO:0004421 hydroxymethylglutaryl-CoA synthase activity | IEA GO_REF:0000120 | ACCEPT | 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. Reason: Duplicate of the experimentally/phylogenetically supported core MF; the EC and RHEA mappings are exactly correct. Supporting Evidence: file:human/HMGCS1/HMGCS1-uniprot.txt EC=2.3.3.10 |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasmic localization from the UniProt subcellular-location vocabulary mapping, consistent with the curated location of this cytosolic enzyme. Reason: HMGCS1 is a soluble cytosolic protein; cytoplasm is correct (the more specific cytosol term is also annotated). Supporting Evidence: file:human/HMGCS1/HMGCS1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0006084 acetyl-CoA metabolic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO assignment of acetyl-CoA metabolic process, duplicating the IBA of the same term. Reason: Accurate (acetyl-CoA is a substrate) but generic; keep as non-core, consistent with the IBA annotation of the same term. Supporting Evidence: file:human/HMGCS1/HMGCS1-uniprot.txt Catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA |
| GO:0008299 isoprenoid biosynthetic process | IEA GO_REF:0000002 | ACCEPT | 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. 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. Supporting Evidence: Reactome:R-HSA-191323 is involved in synthesis of isoprenoids and cholesterol biosynthesis file:human/HMGCS1/HMGCS1-uniprot.txt (R)-mevalonate from acetyl-CoA: step 2/3. |
| GO:0016746 acyltransferase activity | IEA GO_REF:0000002 | MODIFY | Summary: Very general acyltransferase (thiolase-like superfamily) activity term from InterPro; HMGCS1's actual transferase activity is the specific HMG-CoA synthase activity. 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 replacements: hydroxymethylglutaryl-CoA synthase activity Supporting Evidence: file:human/HMGCS1/HMGCS1-uniprot.txt EC=2.3.3.10 |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: Bare protein-binding IPI from a large-scale BioPlex 2.0 AP-MS interactome screen (interactor SLC22A5). Not informative about HMGCS1 molecular function. 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). Supporting Evidence: PMID:28514442 BioPlex 2.0 constitutes a powerful resource for biological inquiry |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Bare protein-binding IPI from a large-scale BioPlex 3.0 AP-MS interactome screen. Uninformative about HMGCS1 molecular function. 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. Supporting Evidence: PMID:33961781 These networks model the interactome whose |
| GO:0006695 cholesterol biosynthetic process | TAS Reactome:R-HSA-9969896 | ACCEPT | 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. 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. Supporting Evidence: Reactome:R-HSA-9969896 Cholesterol biosynthesis begins with the transformation of cytosolic acetyl CoA into lanosterol file:human/HMGCS1/HMGCS1-uniprot.txt mevalonate, a precursor for cholesterol synthesis. |
| GO:0004421 hydroxymethylglutaryl-CoA synthase activity | TAS Reactome:R-HSA-191323 | ACCEPT | Summary: Reactome traceable assertion of the core HMG-CoA synthase reaction (condensation of acetyl-CoA and acetoacetyl-CoA to HMG-CoA). Reason: Duplicate of the core molecular function, supported by the curated Reactome reaction and by experimental characterization. Supporting Evidence: Reactome:R-HSA-191323 catalyzes the condensation of acetyl CoA with acetoacetyl CoA to produce HMG-CoA |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | MARK AS OVER ANNOTATED | Summary: Nucleoplasm localization from an HPA immunofluorescence dataset. HMGCS1 is a soluble cytosolic mevalonate-pathway enzyme, so nucleoplasm is not a core location. 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. Supporting Evidence: file:human/HMGCS1/HMGCS1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Cytosol localization from HPA immunofluorescence, matching the curated cytosolic location of this soluble enzyme. Reason: Cytosol is the correct and most specific subcellular location for HMGCS1. Supporting Evidence: file:human/HMGCS1/HMGCS1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: file:human/HMGCS1/HMGCS1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0006695 cholesterol biosynthetic process | IC PMID:7911016 Molecular cloning and nucleotide sequence of complementary D... | ACCEPT | 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. 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. Supporting Evidence: file:human/HMGCS1/HMGCS1-uniprot.txt mevalonate, a precursor for cholesterol synthesis. |
| GO:0042803 protein homodimerization activity | IDA PMID:20346956 Crystal structures of human HMG-CoA synthase isoforms provid... | ACCEPT | Summary: HMGCS1 is a homodimer, established by the crystal structure of the human cytosolic isoform (PDB 2P8U). Reason: Directly supported by the crystallographic and biochemical characterization showing HMGCS1 functions as a homodimer. Supporting Evidence: PMID:20346956 we report high-resolution crystal structures of the human cytosolic file:human/HMGCS1/HMGCS1-uniprot.txt SUBUNIT: Homodimer. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1655848 | ACCEPT | Summary: Reactome traceable assertion of cytosolic localization, consistent with the curated location. Reason: Cytosol is the correct core location for this soluble mevalonate-pathway enzyme. Supporting Evidence: file:human/HMGCS1/HMGCS1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-191323 | ACCEPT | Summary: Reactome traceable assertion of cytosolic localization (duplicate of the Reactome/HPA cytosol annotations). Reason: Correct core location; consistent with the other cytosol annotations. Supporting Evidence: file:human/HMGCS1/HMGCS1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0006629 lipid metabolic process | NAS PMID:7913309 Human cytoplasmic 3-hydroxy-3-methylglutaryl coenzyme A synt... | MARK AS OVER ANNOTATED | Summary: Very general lipid metabolic process assertion. HMGCS1's role is captured far more precisely by the cholesterol/isoprenoid biosynthetic process terms. 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. Supporting Evidence: file:human/HMGCS1/HMGCS1-uniprot.txt mevalonate, a precursor for cholesterol synthesis. |
| GO:0004421 hydroxymethylglutaryl-CoA synthase activity | TAS PMID:7913309 Human cytoplasmic 3-hydroxy-3-methylglutaryl coenzyme A synt... | ACCEPT | Summary: Traceable assertion of HMG-CoA synthase activity from the biochemical characterization of recombinant human cytoplasmic HMGCS1. Reason: Directly supported by expression/purification/kinetics and by Cys129 mutagenesis abolishing activity. This is the core molecular function. Supporting Evidence: PMID:7913309 Mutation of Cys129 to serine or alanine destroys |
| GO:0005737 cytoplasm | TAS PMID:7913309 Human cytoplasmic 3-hydroxy-3-methylglutaryl coenzyme A synt... | ACCEPT | Summary: Traceable assertion of cytoplasmic localization, consistent with the curated cytosolic location. Reason: HMGCS1 is a cytoplasmic/cytosolic enzyme; correct localization. Supporting Evidence: file:human/HMGCS1/HMGCS1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
Loading supporting content…
Download this section (compressed HTML)Q: 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?
Q: 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?
Experiment: 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.
Experiment: Metabolic flux analysis in HMGCS1-deficient patient muscle/cells to quantify the mevalonate/cholesterol-pathway defect and its rescue by exogenous mevalonate.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)