Hydroxymethylglutaryl-CoA synthase (HMG-CoA synthase) (HMGCS)

Human Hydroxymethylglutaryl-CoA synthase (HMG-CoA synthase) is a vital enzyme in lipid metabolism, existing as two distinct isoforms: the cytosolic HMGCS1 and the mitochondrial HMGCS2 [UniProt P35914, P54868]. HMGCS1 serves as the first committed step in the mevalonate pathway, which is responsible for the synthesis of cholesterol, isoprenoids, and other essential lipids [PubMed: 28256237]. In contrast, HMGCS2 is primarily expressed in the liver and acts as the rate-limiting enzyme for ketogenesis, converting acetyl-CoA into ketone bodies to provide energy during fasting or metabolic stress [PubMed: 24075023]. Dysregulation of HMGCS1 is often observed in various cancers, where it supports rapid cell proliferation by ensuring a steady supply of cholesterol [PubMed: 30633913]. Conversely, genetic mutations in HMGCS2 lead to HMG-CoA synthase deficiency, a rare metabolic disorder characterized by life-threatening hypoketotic hypoglycemia [NIH: Genetic and Rare Diseases Information Center]. While HMG-CoA reductase is the primary target for statins, HMG-CoA synthase is an attractive alternative target for treating hyperlipidemia and metabolic syndrome. Experimental inhibitors like hymeglusin (F-244) have demonstrated potent and selective inhibition of this enzyme, though they are currently used primarily in research settings rather than clinical practice [PubMed: 15590645].

Other names

3-hydroxy-3-methylglutaryl-CoA synthaseHMGCS1HMGCS23-hydroxy-3-methylglutaryl-Coenzyme A synthaseHMGCS

Inhibition of the condensation of acetyl-CoA with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) by targeting the active site cysteine residue [PubMed: 15590645].