HMGCS1
3-Hydroxy-3-Methylglutaryl-CoA Synthase 1
Gene Information Card
| Symbol | HMGCS1 |
|---|---|
| Full Name | 3-hydroxy-3-methylglutaryl-CoA synthase 1 |
| Gene Type | protein-coding |
| Chromosomal Location | 5p12 |
| NCBI Gene ID | 3157 ncbi.nlm.nih.gov/gene/3157 |
| Ensembl ID | ENSG00000112972 |
| UniProt ID | Q01581 |
| OMIM ID | 142910 |
| HGNC ID | 5007 |
| Aliases | HMGCS, HMG-CoA synthase, HMGCS1 |
Description
HMGCS1 encodes the cytosolic enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 1, which catalyzes the condensation of acetyl-CoA and acetoacetyl-CoA to form HMG-CoA, the second committed step in the mevalonate pathway. This pathway is essential for cholesterol biosynthesis and the production of isoprenoids, including ubiquinone, dolichol, and prenylated proteins. The enzyme is regulated by sterol regulatory element-binding proteins (SREBPs) and is a target for statin therapy.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Mevalonate kinase deficiency | Loss-of-function mutations in HMGCS1 are not directly linked; however, defects in the mevalonate pathway cause autoinflammatory syndromes. HMGCS1 deficiency is not a known disease in humans. | No direct evidence; pathway inference from OMIM #610377. |
| Hypercholesterolemia | Upregulation of HMGCS1 contributes to increased cholesterol synthesis. Polymorphisms may influence lipid levels. | ClinVar and GWAS studies (PMID: 24097068). |
| Cancer (various) | Overexpression of HMGCS1 supports mevalonate pathway flux required for tumor cell proliferation. | COSMIC database; expression data in multiple cancer types. |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | 12.5 | High |
| Adrenal gland | 8.3 | Medium |
| Small intestine | 6.1 | Medium |
| Kidney | 4.2 | Medium |
| Brain | 1.8 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 | 15.2 | Hepatocellular carcinoma cell line; high expression |
| A549 | 9.8 | Lung adenocarcinoma cell line; medium expression |
| MCF7 | 7.5 | Breast cancer cell line; medium expression |
| K562 | 3.1 | Leukemia cell line; low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1072C>T (p.Arg358Trp) | Missense | <0.01% | Unknown; rare variant in population databases |
| c.1246G>A (p.Val416Met) | Missense | <0.01% | Unknown; predicted benign by in silico tools |
| c.1A>G (p.Met1Val) | Start loss | <0.01% | Likely loss of function; not reported in disease |
Mutation functional classification
Loss of Function (LOF)
No confirmed loss-of-function mutations in human disease; knockout in mice is embryonic lethal.
Gain of Function (GOF)
Not described.
Dominant Negative (DN)
Not described.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Mevalonate pathway (KEGG: hsa00900)
• Cholesterol biosynthesis (Reactome: R-HSA-191273)
• Metabolism of lipids (Reactome: R-HSA-556833)
Protein Summary
HMGCS1 is a 520-amino-acid cytosolic enzyme that catalyzes the condensation of acetyl-CoA and acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). This reaction is the second committed step in the mevalonate pathway, which is critical for cholesterol and isoprenoid biosynthesis. The enzyme is highly expressed in liver and adrenal tissues and is regulated by SREBP transcription factors. Its activity is inhibited by statins indirectly via reduced HMGCR activity. No disease-causing mutations have been reported in humans, but overexpression is observed in several cancers.
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