3-hydroxy-3-methylglutaryl-CoA synthase 2 (mitochondrial) (HMGCS2)

3-hydroxy-3-methylglutaryl-CoA synthase 2 (mitochondrial) is a mitochondrial enzyme encoded by the HMGCS2 gene, catalyzing the first irreversible and rate-limiting step in ketogenesis—the process by which fatty acids are converted into ketone bodies, providing an alternative energy source during fasting or carbohydrate restriction. This enzyme is crucial for metabolic adaptation in the liver and other tissues when glucose is unavailable, and its activity is tightly regulated by deacetylation (through SIRT3), nutritional states, and potentially other posttranslational mechanisms. Mutations lead to HMG-CoA synthase deficiency, a rare metabolic disorder characterized by inability to generate ketone bodies, leading to risk of hypoglycemia, heart and neurological complications, particularly during times of high energy demand. HMGCS2 expression patterns and functional roles are also associated with metabolic reprogramming in cancer; upregulation may promote tumor suppression in renal cell carcinoma, while altered expression is implicated in prostate cancer progression. While there are currently no approved drugs that directly target HMGCS2, its expression, activity, and posttranslational regulation are implicated as biomarkers and possible future therapeutic targets for metabolic and cancer disorders.

Other names

Hydroxymethylglutaryl-CoA synthase, mitochondrialHMG-CoA synthase3-hydroxy-3-methylglutaryl coenzyme A synthase3-hydroxy-3-methylglutaryl-Coenzyme A synthase 2 (mitochondrial)Testicular tissue protein Li 88EC 2.3.3.10HMGCS2

Enzyme activation/inhibition: Agents modulate HMGCS2 activity, impacting ketone body production and downstream metabolic effects. Cancer biology: Upregulation suppresses proliferation in renal carcinoma and may interact with FGF21 signaling. Nutrient sensing: Activity regulated by posttranslational modification (acetylation/deacetylation via SIRT3). Metabolic pathway modulation: Small-molecule regulators could theoretically act through mitochondrial enzyme modulation, but no clinical agents are cited.