Acetyl-CoA synthetase short-chain family (ACSS) (ACSS)

The Acetyl-CoA synthetase short-chain (ACSS) family consists of enzymes that catalyze the conversion of acetate and coenzyme A (CoA) into acetyl-CoA, a central metabolite in energy production and biosynthesis (UniProt, 2024). In humans, this family includes three members: ACSS1, ACSS2, and ACSS3. ACSS2 is the most extensively studied therapeutic target; it is located in the cytoplasm and nucleus, where it provides acetyl-CoA for de novo lipogenesis and histone acetylation, particularly under metabolic stress or hypoxia (PubMed, PMID: 28552616). ACSS1 and ACSS3 are localized to the mitochondria and primarily facilitate the oxidation of acetate for the tricarboxylic acid (TCA) cycle (PubMed, PMID: 31434671). In many cancers, ACSS2 is upregulated to allow tumors to utilize acetate as an alternative carbon source when glucose or glutamine is scarce (Nature, 2014). Consequently, inhibiting ACSS family members, particularly ACSS2, is being explored as a strategy to starve cancer cells and modulate epigenetic signaling (PubMed, PMID: 33053371). This family represents a critical link between metabolism and gene expression, making it a focal point for developing novel anti-cancer and metabolic therapies.

Other names

Acetate--CoA ligaseAcetyl-activating enzymeAceCSShort-chain acyl-CoA synthetaseACSS1ACSS2ACSS3

Inhibition of the ATP-dependent ligation of acetate and coenzyme A to form acetyl-CoA, thereby depleting the pool of acetyl-CoA available for lipid synthesis and histone acetylation.