Role of long-chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling.
The intracellular concentration of free unbound acyl-CoA esters is tightly 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 physiological conditions the free cytosolic concentration of acyl-CoA esters 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 carboxylase is active during fatty acid synthesis (Ki 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 reported experiments on the effects of acyl-CoA on cellular functions and 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 required. However, the observations that the ryanodine-senstitive Ca2+-release channel is regulated by long-chain acyl-CoA esters in the presence of a molar excess of acyl-CoA binding protein and that acetyl-CoA carboxylase, the AMP kinase kinase and the Escherichia coli transcription factor FadR are affected by low nanomolar concentrations of acyl-CoA indicate that long-chain acyl-CoA esters can act as regulatory molecules in vivo. This view is further supported by the observation that fatty acids do not repress expression of acetyl-CoA carboxylase or Delta9-desaturase in yeast deficient in acyl-CoA synthetase.
Faergeman
N J
NJ
Institute of Biochemistry, Odense University, DK-5230 Odense, Denmark.
Knudsen
J
J
D000214:Acyl Coenzyme A / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology; D002450:Cell Communication / Q000502:physiology*; D003066:Coenzyme A Ligases / Q000378:metabolism; D026261:Diazepam Binding Inhibitor; D004734:Energy Metabolism; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids / Q000502:physiology; D006801:Humans; D008055:Lipids / Q000096:biosynthesis; D008954:Models, Biological; D008969:Molecular Sequence Data; D018996:Myelin P2 Protein / Q000502:physiology; D009363:Neoplasm Proteins; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins
D000214:Acyl Coenzyme A; D002352:Carrier Proteins; D026261:Diazepam Binding Inhibitor; C107608:FABP7 protein, human; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D008055:Lipids; D018996:Myelin P2 Protein; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D011493:Protein Kinase C; D003066:Coenzyme A Ligases