Fatty acid synthase beta-ketoacyl-ACP synthase domain (FASN KS domain)

Fatty acid synthase (FASN) is a large homodimeric enzyme responsible for the de novo synthesis of palmitate from acetyl-CoA and malonyl-CoA (UniProt: P49327). The beta-ketoacyl-ACP synthase (KS) domain is the essential catalytic component that performs the condensation reaction, adding two-carbon units to the growing fatty acid chain (PMID: 17350611). While FASN expression is low in most normal tissues, it is significantly upregulated in various cancers to support rapid membrane synthesis and energy production, and in metabolic diseases like nonalcoholic steatohepatitis (NASH) where it contributes to hepatic steatosis (PMID: 27105801, PMID: 32054750). Therapeutic strategies targeting the KS domain involve small-molecule inhibitors that bind to the active site, effectively blocking the entire lipogenic pathway. Clinical candidates like denifanstat (TVB-2640) have demonstrated efficacy in reducing liver fat and inhibiting tumor growth in clinical trials (PMID: 34133849). However, because FASN is active in sebaceous glands, common side effects of these inhibitors include dry skin, dry eyes, and hair loss (PMID: 29453255).

Other names

3-oxoacyl-[acyl-carrier-protein] synthaseBeta-ketoacyl synthaseKS domain of FASNBeta-ketoacyl-acyl carrier protein synthaseKetoacyl synthase

Inhibition of the condensation reaction between an acyl group and malonyl-ACP, preventing the elongation of the fatty acid chain during de novo lipogenesis.