Catalyzes the conversion of long-chain fatty acids to their active form acyl-CoAs for both synthesis of cellular lipids, and degradation via beta-oxidation (PubMed:28209804). ACSL5 may sensitize epithelial cells to apoptosis specifically triggered by the death ligand TRAIL at the villus tip of the crypt-villus axis of the small intestine (By similarity). May have a role in the survival of glioma cells (By similarity). May activate fatty acids from exogenous sources for the synthesis of triacylglycerol destined for intracellular storage. It was suggested that it may also stimulate fatty acid oxidation. Utilizes a wide range of saturated fatty acids with a preference for C16-C18 unsaturated fatty acids. a long-chain fatty acid + ATP + CoA = a long-chain fatty acyl-CoA + AMP + diphosphate (5Z,8Z,11Z,14Z)-eicosatetraenoate + ATP + CoA = (5Z,8Z,11Z,14Z)-eicosatetraenoyl-CoA + AMP + diphosphate 15-hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoate + ATP + CoA = 15-hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoyl-CoA + AMP + diphosphate 12-hydroxy-(5Z,8Z,10E,14Z)-eicosatetraenoate + ATP + CoA = 12-hydroxy-(5Z,8Z,10E,14Z)-eicosatetraenoyl-CoA + AMP + diphosphate 5-hydroxy-(6E,8Z,11Z,14Z)-eicosatetraenoate + ATP + CoA = 5-hydroxy-(6E,8Z,11Z,14Z)-eicosatetraenoyl-CoA + AMP + diphosphate 14,15-epoxy-(5Z,8Z,11Z)-eicosatrienoate + ATP + CoA = 14,15-epoxy-(5Z,8Z,11Z)-eicosatrienoyl-CoA + AMP + diphosphate 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoate + ATP + CoA = 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoyl-CoA + AMP + diphosphate ATP + CoA + hexadecanoate = AMP + diphosphate + hexadecanoyl-CoA (E)-hexadec-2-enoate + ATP + CoA = (2E)-hexadecenoyl-CoA + AMP + diphosphate Expressed most abundantly in the small intestine, and to a much lesser extent in the lung, liver, adrenal gland, adipose tissue and kidney. Expression decreases in response to fast and increases after high sucrose diet. 5 rat isozymes encoded by different genes have been described. ACSL6 corresponds to isozyme 2 (ACS2). Belongs to the ATP-dependent AMP-binding enzyme family.