Long-chain acyl-CoA synthetase (ACSL) (ACSL)

Long-chain acyl-CoA synthetases (ACSLs) are a family of enzymes, comprising five isoforms (ACSL1, ACSL3, ACSL4, ACSL5, and ACSL6), that catalyze the conversion of free long-chain fatty acids (C12–C22) into fatty acyl-CoA esters [PubMed: 31344914]. This reaction is the first and committed step in fatty acid metabolism, directing fatty acids toward either mitochondrial beta-oxidation for energy production or the synthesis of complex lipids such as phospholipids and triacylglycerols [PubMed: 31344914, PubMed: 34153351]. ACSLs are critical regulators of various cellular processes, including ferroptosis (specifically ACSL4), steroidogenesis, and protein acylation [PubMed: 28106078, PubMed: 31344914]. In clinical contexts, ACSLs are frequently dysregulated in cancers, metabolic disorders like diabetes and obesity, and cardiovascular diseases, where they contribute to disease progression by altering lipid homeostasis [PubMed: 31344914, PubMed: 35832041]. Pharmacological targeting of ACSLs, particularly through inhibitors like Triacsin C or selective ACSL4 inhibitors, is being explored as a strategy to disrupt cancer cell metabolism and modulate inflammatory responses [PubMed: 15699031, PubMed: 31344914]. However, the widespread physiological importance of these enzymes across different tissues presents significant challenges for drug development, particularly regarding systemic toxicity and the need for isoform-specific selectivity [PubMed: 31344914, PubMed: 35832041].

Other names

Long-chain-fatty-acid-CoA ligaseLC-FACSLACSAcyl-CoA synthetase long-chain family

Competitive inhibition of the fatty acid binding pocket, preventing the activation of long-chain fatty acids into fatty acyl-CoA esters.