ROLE OF LONG-CHAIN FATTY ACYL-COA ESTERS IN THE REGULATION OF METABOLISM AND IN CELL SIGNALING

The intracellular concentration of free unbound acyl-CoA esters is tig htly controlled by feedback inhibition of the acyl-CoA synthetase and is buffered by specific acyl-CoA binding proteins. Excessive increases in the concentration are expected to be prevented by conversion into acylcarnitines or by hydrolysis by acyl-CoA hydrolases. Under normal p hysiological conditions the free cytosolic concentration of acyl-CoA e sters will be in the low nanomolar range, and it is unlikely to exceed 200 nM under the most extreme conditions. The fact that acetyl-CoA ca rboxylase is active during fatty acid synthesis (K-1 for acyl-CoA is 5 nM) indicates strongly that the free cytosolic acyl-CoA concentration is below 5 nM under these conditions. Only a limited number of the re ported experiments on the effects of acyl-CoA on cellular functions an d enzymes have been carried out at low physiological concentrations in the presence of the appropriate acyl-CoA-buffering binding proteins. Re-evaluation of many of the reported effects is therefore urgently re quired. However, the observations that the ryanodine-senstitive Ca2+-r elease channel is regulated by long-chain acyl-CoA esters in the prese nce of a molar excess of acyl-CoA binding protein and that acetyl-CoA carboxylase, the AMP kinase kinase and the Escherichia coli transcript ion factor FadR are affected by low nanomolar concentrations of acyl-C oA indicate that long-chain acyl-CoA esters can act as regulatory mole cules in vivo. This view is further supported by the observation that fatty acids do not repress expression of acetyl-CoA carboxylase or Del ta(9)-desaturase in yeast deficient in acyl-CoA synthetase.