Triacsin C: a differential inhibitor of arachidonoyl-CoA synthetase and nonspecific long chain acyl-CoA synthetase.
Triacsins A, B, C, and D are newly discovered compounds isolated from the culture filtrate of streptomyces which are known to inhibit nonspecific long chain acyl-CoA synthetase (EC 6.2.1.3.). These inhibitors have not been previously studied with regard to their effects on arachidonoyl-CoA synthetase, an enzyme which specifically utilizes arachidonate and other icosanoid precursor fatty acids. To explore this question, we used triacsin C, a potent inhibitor of the nonspecific acyl-CoA synthetase. Triacsin C was found to inhibit the action of arachidonoyl-CoA synthetase and the nonspecific enzyme in sonicates of HSDM1C1 mouse fibrosarcoma cells. Importantly, however, the triacsin concentration and length of pre-incubation with the enzymes could be adjusted to almost completely inhibit (greater than 80%) the nonspecific long chain acyl CoA-synthetase, with less than 20% inhibition of arachidonoyl-CoA synthetase. Using intact cultured cells exposed to 1 ug/ml triacsin for up to 15 minutes, we unexpectedly observed preferential inhibition of arachidonoyl-CoA synthetase activity. In intact cell studies, arachidonoyl-CoA synthetase was inhibited greater than 90%, with 55-60% inhibition of the nonspecific acyl-CoA synthetase. As additional evidence of its inhibition of acyl-CoA synthetase enzymes in intact cells, triacsin C inhibited both fatty acid uptake into cells and icosanoid production, metabolic processes which in certain cell types appear to be dependent on acyl-CoA synthetase activity. Thus, triacsin C is a novel inhibitor which can alter the fatty metabolism of intact cells. This compound can be of significant value in determining the specific cellular functions of the two acyl-CoA synthetase enzymes.
Hartman
E J
EJ
Dept. of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia 19104.
Omura
S
S
Laposata
M
M
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001692:Biological Transport; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors*; D015232:Dinoprostone / Q000096:biosynthesis; D005354:Fibrosarcoma / Q000473:pathology; D051379:Mice; D019301:Oleic Acid; D009829:Oleic Acids / Q000378:metabolism; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014226:Triazenes / Q000494:pharmacology*; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
D001095:Arachidonic Acids; D009829:Oleic Acids; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014226:Triazenes; D016718:Arachidonic Acid; D019301:Oleic Acid; C034613:triacsin C; D003066:Coenzyme A Ligases; C033896:arachidonate - CoA ligase; C090799:FAA2 protein, S cerevisiae; D000098859:Long-Chain-Fatty-Acid-CoA Ligase; D015232:Dinoprostone