3-hydroxy-3-methylglutaryl-CoA synthase (HMG-CoA synthase)

3-hydroxy-3-methylglutaryl-CoA synthase is an enzyme (EC 2.3.3.10) that catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)[1][2][7][8]. In eukaryotes, it exists in two main isoforms: the mitochondrial form (HMGCS2), responsible for ketone body synthesis, and the cytosolic form (HMGCS1), the first committed step in the mevalonate pathway leading to the synthesis of cholesterol and isoprenoids[1][7][8]. In bacteria, particularly Gram-positive pathogens, it participates in a mevalonate pathway essential for survival, making it a target for novel antibiotics[3][4]. Its dysfunction is implicated in metabolic disorders and it is being explored as a therapeutic target in both cardiovascular and infectious diseases.

Other names

Hydroxymethylglutaryl-CoA synthaseHMGCSHMG-CoA synthase, cytoplasmic (HMGCS1, for cytosolic isoform)HMG-CoA synthase, mitochondrial (HMGCS2, for mitochondrial isoform)3-hydroxy-3-methylglutaryl coenzyme A synthase

Inhibition of HMG-CoA synthase would block mevalonate pathway flux and ketone body biosynthesis, potentially lowering cholesterol synthesis or depriving certain bacteria of essential isoprenoids[2][3][4].