Catalyzes the conversion of long-chain fatty acids to their active form acyl-CoA for both synthesis of cellular lipids, and degradation via beta-oxidation (PubMed:28209804, PubMed:23766516, PubMed:9096315). Preferentially activates arachidonate and eicosapentaenoate as substrates (PubMed:9096315). Preferentially activates 8,9-EET > 14,15-EET > 5,6-EET > 11,12-EET (PubMed:23766516). Modulates glucose-stimulated insulin secretion by regulating the levels of unesterified EETs (PubMed:23766516). Modulates prostaglandin E2 secretion (By similarity). 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 5,6-epoxy-(8Z,11Z,14Z)-eicosatrienoate + ATP + CoA = 5,6-epoxy-(8Z,11Z,14Z)-eicosatrienoyl-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 8,9-epoxy-(5Z,11Z,14Z)-eicosatrienoate + ATP + CoA = 8,9-epoxy-(5Z,11Z,14Z)-eicosatrienoyl-CoA + AMP + diphosphate ATP + CoA + hexadecanoate = AMP + diphosphate + hexadecanoyl-CoA (E)-hexadec-2-enoate + ATP + CoA = (2E)-hexadecenoyl-CoA + AMP + diphosphate Both triacsin C and rosiglitazone inhibit arachidonoyl-CoA ligase activity. Expression is decreased by polyunsaturated fatty acid (PUFA). 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.