ATP-citrate synthase (ACLY)

ATP-citrate synthase (ACLY) is a critical cytosolic enzyme that catalyzes the ATP-dependent conversion of citrate and Coenzyme A (CoA) into oxaloacetate and acetyl-CoA (UniProt P53396). This reaction serves as a vital bridge between carbohydrate metabolism and lipid synthesis, providing the essential acetyl-CoA building blocks for both de novo lipogenesis and cholesterol biosynthesis (PubMed: 22613149). In addition to its metabolic role, ACLY-derived acetyl-CoA is a major substrate for histone acetylation, thereby influencing epigenetic regulation and gene expression in response to nutrient availability (PubMed: 19461003). Clinically, ACLY is a validated therapeutic target for cardiovascular disease; its inhibition by drugs like bempedoic acid leads to a reduction in hepatic cholesterol synthesis and a compensatory upregulation of LDL receptors, which effectively lowers circulating LDL-C levels (FDA: Nexletol Label). Furthermore, ACLY is often upregulated in various malignancies to support the lipid requirements of rapidly proliferating tumor cells, positioning it as a potential target for anti-cancer therapy (PubMed: 28801540). Therapeutic challenges associated with ACLY inhibition include potential elevations in serum uric acid levels, which can predispose patients to gout.

Other names

ATP-citrate lyaseCitrate cleavage enzymeACLACLYD

Inhibition of the enzymatic conversion of citrate and CoA into acetyl-CoA and oxaloacetate