Long-chain acyl-CoA synthetase (ACSL)

Long-chain acyl-CoA synthetase (ACSL) is a family of enzymes that catalyze the conversion of free long-chain fatty acids into fatty acyl-CoA esters, a prerequisite for their entry into most metabolic pathways (UniProt: P33121). This activation step is essential for fatty acid oxidation, the synthesis of complex lipids such as phospholipids and triglycerides, and the regulation of lipid-mediated signaling (PubMed: 21185227). In humans, the family comprises five distinct isoforms—ACSL1, ACSL3, ACSL4, ACSL5, and ACSL6—which differ in their tissue expression patterns and substrate specificities (NCBI Gene: 2180). ACSL4, in particular, has gained prominence as a critical pro-ferroptotic factor, as it enriches membranes with long-chain polyunsaturated fatty acids susceptible to peroxidation (PubMed: 28065414). Dysregulation of these enzymes is frequently observed in metabolic diseases, including obesity, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD), as well as in various cancers where they support rapid membrane synthesis and energy production (PubMed: 30107179). Therapeutic targeting of ACSL isoforms is being investigated for treating insulin resistance and inhibiting tumor growth, with compounds like Triacsin C serving as potent, though often non-selective, inhibitors (PubChem: CID 104597). However, the high degree of homology between isoforms and their vital roles in systemic lipid homeostasis present significant challenges for drug development and safety (PubMed: 24847880).

Other names

Long-chain fatty acid-CoA ligaseFACLLACSAcyl-CoA synthetase long-chain family

Catalyzes the ATP-dependent conversion of long-chain fatty acids to fatty acyl-CoA esters, facilitating their utilization in metabolic and signaling pathways (UniProt: P33121).