Acetyl-coenzyme A acetyltransferase (ACAT) (ACAT)

Acetyl-coenzyme A acetyltransferase (ACAT), also known as acetoacetyl-CoA thiolase or Thiolase II, is a fundamental metabolic enzyme that catalyzes the reversible condensation of two acetyl-CoA molecules into acetoacetyl-CoA [6]. In humans, it exists as two distinct isoforms: the mitochondrial ACAT1 and the cytosolic ACAT2 [2, 16]. ACAT1 plays a central role in ketone body metabolism (ketogenesis and ketolysis) and the catabolism of branched-chain amino acids like isoleucine, while ACAT2 provides the substrate for the mevalonate pathway, the rate-limiting step in cholesterol biosynthesis [6, 16, 21]. Recent research has highlighted ACAT1 as a significant therapeutic target in oncology; it acts as a protein acetyltransferase that modifies the pyruvate dehydrogenase (PDH) complex, thereby inhibiting oxidative phosphorylation and promoting the Warburg effect in cancer cells [2, 13]. Inhibiting ACAT1 with compounds such as arecoline has shown promise in suppressing tumor growth and enhancing anti-tumor immunity [1, 13]. It is crucial to distinguish this enzyme from the similarly named acyl-CoA:cholesterol acyltransferase (SOAT), which is also frequently abbreviated as ACAT but functions in cholesterol esterification and has been the target of cardiovascular drugs like avasimibe [15, 18].

Other names

Acetoacetyl-CoA thiolaseThiolase II3-oxothiolaseBeta-ketothiolaseAcetyl-CoA C-acetyltransferase

Inhibition of the reversible conversion between acetyl-CoA and acetoacetyl-CoA; inhibition of protein acetylation (e.g., PDH) to restore oxidative phosphorylation in cancer cells; inhibition of cholesterol esterification (for SOAT-targeting analogs).