Inhibition of citrate synthase by oleoyl-CoA: a regulatory phenomenon.
Fatty acyl-CoAs are good detergents (dritical micelle concentrations = 3-4 muM) and can inhibit a number of enzymes, including some involved in fatty acid biosynthesis. The regulatory significance of fatty acyl-CoAs as negative effectors has been questioned largely because of the difficulties in distinguishing possible nonspecific detergent effects from more specific regulatory interactions with these enzymes. A new analogue of oleoyl-CoA, oleoyl-(1, N6-etheno)-CoA, is a better detergent (critical micelle concentration = 3.2 muM) than oleoyl-CoA (critical micelle concentration = 4.7 muM). This new analogue is not as good (by an order of magnitude) an inhibitor of citrate synthase [citrate oxaloacetatelyase (pro-3S-CH2-COO-vectoracetyl-CoA); EC 4.1.3.7] nor is it bound as well oleoyl-CoA. Since the only difference between these two compounds is substitution of 1,N6-ethenoadenine for the adenine of CoA, the difference in inhibition and binding implies a specific interaction between the adenine moiety of oleoyl-CoA and citrate synthase. Moreover, since oleoyl-(1,N6-etheno)CoA is a better detergent than oleoyl-CoA, the detergency of oleoyl-CoA is not the sole cause of the fatty acyl-CoA inhibition of citrate synthase. These results support a physiological role for oleoyl-CoA as a negative effector for citrate synthase. An analogous physiological role for fatty acyl-CoA as negative effectors for other enzymes seems reasonable.
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002950:Citrate (si)-Synthase / Q000037:antagonists & inhibitors*; D003065:Coenzyme A / Q000494:pharmacology*; D007700:Kinetics; D009206:Myocardium / Q000201:enzymology; D009829:Oleic Acids / Q000494:pharmacology; D007652:Oxo-Acid-Lyases / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D013552:Swine
D009829:Oleic Acids; D002950:Citrate (si)-Synthase; D007652:Oxo-Acid-Lyases; D003065:Coenzyme A