Fatty acyl-CoA inhibits 1-alkyl-sn-glycero-3-phosphate acetyltransferase in microsomes of immature rabbit cerebral cortex: control of the first committed step in the de novo pathway of platelet-activating factor synthesis.
Microsomal fractions of cerebral cortices of 15-day-old rabbits were used to study the 1-alkyl-sn-glycero-3-phosphate (AGP) acetyltransferase that generates 1-alkyl-2-acetyl-sn-glycero-3-phosphate in the de novo path of platelet-activating factor synthesis. The AGP acetyltransferase activity was inhibited by small concentrations of medium-long chain fatty acyl-CoA thioesters. In contrast, the AGP acyltransferase used oleoyl-CoA as substrate and was not inhibited by the presence of acetyl-CoA in high molar excess. The inhibition of AGP acetyltransferase was seen at concentrations of oleoyl-CoA as low as 0.5 microM using 12.5 microM AGP and 200 microM acetyl-CoA. The inhibition by oleoyl-CoA was noncompetitive for the acetyl-CoA substrate. However, there was evidence that the oleoyl-CoA was competing with AGP in the acetyltransferase reaction, as the inhibition was lessened by increasing the AGP substrate concentration. Several acyl-CoA thioesters were effective as inhibitors of the AGP acetyltransferase, including oleoyl-, palmitoyl-, lauroyl-, and octanoyl-CoA. Propionyl- and butyryl-CoA were less effective as inhibitors, and propionyl-CoA was found to be a competitive inhibitor for acetyl-CoA. We have noted earlier that MgATP is an effective inhibitor of the AGP acetyltransferase and here we show that the inhibition by oleoyl-CoA can be increased by the presence of 0.1 mM MgATP. In brain ischemia, a decline in ATP levels would likely lead to a corresponding fall in acyl-CoA concentrations, thereby relieving the inhibition of AGP acetyltransferase and permitting the flow of AGP into the de novo pathway of platelet-activating factor synthesis.
Baker
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RR
Department of Medicine, University of Toronto, Ontario, Canada.
Chang
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D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; D000214:Acyl Coenzyme A / Q000494:pharmacology*; D000217:Acyltransferases / Q000032:analysis / Q000037:antagonists & inhibitors*; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000201:enzymology* / Q000378:metabolism / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D004952:Esters / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology; D008861:Microsomes / Q000201:enzymology* / Q000648:ultrastructure; D010972:Platelet Activating Factor / Q000378:metabolism* / Q000502:physiology; D011817:Rabbits
D000214:Acyl Coenzyme A; D004952:Esters; D005227:Fatty Acids; D010972:Platelet Activating Factor; C017585:oleoyl-coenzyme A; D000255:Adenosine Triphosphate; D000217:Acyltransferases; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase