Hydroxymethylglutaryl-CoA synthase, mitochondrial (HMGCS2) (HMGCS2)

Hydroxymethylglutaryl-CoA synthase, mitochondrial (HMGCS2) is the rate-limiting enzyme in the ketogenic pathway, responsible for condensing acetoacetyl-CoA and acetyl-CoA to form HMG-CoA within the mitochondrial matrix [1.1.1, 1.3.1]. This process is essential for the production of ketone bodies, such as beta-hydroxybutyrate and acetoacetate, which provide a critical alternative energy source for extrahepatic tissues like the brain and heart during periods of glucose scarcity [1.1.1, 1.5.2]. Beyond its catalytic role, HMGCS2 acts as a transcriptional coactivator for peroxisome proliferator-activated receptor alpha (PPARα), creating a feed-forward regulatory loop that enhances fatty acid oxidation [1.1.3, 1.1.4]. Clinically, loss-of-function mutations in HMGCS2 lead to a rare metabolic disorder characterized by hypoketotic hypoglycemia, metabolic acidosis, and steatotic liver damage [1.3.1, 1.5.2]. In oncology, HMGCS2 is frequently downregulated in hepatocellular and colorectal carcinomas, where it may function as a metabolic tumor suppressor, whereas its upregulation in aggressive prostate cancers suggests a role in metabolic reprogramming to support tumor progression [1.1.3, 1.2.5, 1.3.3]. While no direct HMGCS2-targeting drugs are currently FDA-approved, small-molecule inhibitors like hymeglusin are used in research, and the enzyme's activity is indirectly modulated by metabolic therapies such as SGLT2 inhibitors and PPARα agonists [1.1.1, 1.5.2].

Other names

3-hydroxy-3-methylglutaryl-CoA synthase 2 [1.3.1, 1.4.1]HMG-CoA synthase 2 [1.1.1, 1.4.1]Mitochondrial HMG-CoA synthase [1.3.2, 1.4.1]

Irreversible inhibition through covalent binding to the active-site cysteine residue (e.g., Hymeglusin) [1.1.1] or transcriptional modulation via PPAR-alpha activation (e.g., Fibrates) [1.1.1, 1.1.4].