Catalyzes the first irreversible step in ketogenesis, condensing acetyl-CoA to acetoacetyl-CoA to form HMG-CoA, which is converted by HMG-CoA reductase (HMGCR) into mevalonate. acetoacetyl-CoA + acetyl-CoA + H2O = (3S)-hydroxy-3-methylglutaryl-CoA + CoA + H(+) Metabolic intermediate biosynthesis; (R)-mevalonate biosynthesis; (R)-mevalonate from acetyl-CoA: step 2/3. Homodimer. Liver and kidney. Succinylated. Desuccinylated by SIRT5. Succinylation, at least at Lys-83 and Lys-310, inhibits the enzymatic activity. Belongs to the thiolase-like superfamily. HMG-CoA synthase family.