Fatty acid synthase, keto-reductase domain (FASN-KR)

Fatty acid synthase (FASN) is a large, multi-functional enzyme complex that plays a central role in de novo lipogenesis by converting acetyl-CoA and malonyl-CoA into long-chain fatty acids, primarily palmitate (UniProt P49327). The keto-reductase (KR) domain is one of the essential catalytic components of this complex, responsible for the NADPH-dependent reduction of the 3-ketoacyl intermediate during each cycle of fatty acid elongation (PubMed: 25605953). While FASN expression is generally low in most normal adult tissues, it is significantly upregulated in various cancers and metabolic disorders to meet the increased demand for membrane phospholipids and energy (PubMed: 30103384). Targeting the KR domain with small-molecule inhibitors has emerged as a promising strategy to disrupt lipid metabolism in tumor cells, leading to growth arrest and apoptosis. Additionally, FASN-KR inhibition is being explored for the treatment of metabolic conditions such as non-alcoholic steatohepatitis (NASH) and certain viral infections that rely on host lipid synthesis (ClinicalTrials.gov: NCT04766424). Therapeutic development in this area must address potential side effects, such as skin toxicity, which can occur due to the inhibition of sebum production in sebaceous glands.

Other names

3-oxoacyl-[acyl-carrier-protein] reductaseBeta-ketoacyl-ACP reductaseFASN KR domainKetoacyl reductase

Inhibition of the keto-reductase domain prevents the NADPH-dependent reduction of the 3-oxoacyl intermediate to a 3-hydroxyacyl group, thereby halting the iterative cycle of fatty acid elongation (PubMed: 25605953).