MgATP may depress de novo neuronal nuclear PAF generation by promoting the formation of alkylacylglycerophosphate, an inhibitor of alkylglycerophosphate acetyltransferase.
MgATP substantially inhibited 1-alkyl-sn-glycero-3-phosphate (AGP) acetyltransferase found in neuronal nuclei. Other nucleotides and the ATP analogue AMP-PNP did not show a comparable inhibition. MgATP inhibition decreased in the presence of bovine serum albumin or the fatty acyl CoA synthetase inhibitor, Triacsin C. MgATP inhibition increased when nuclei were preincubated in 50 mM Tris-HCl (pH 7.4)/1 mM MgCl(2) at 37 degrees C, and preincubations elevated levels of nuclear free fatty acid. Exogenous free fatty acid, added to the acetylation incubations, increased the inhibition seen in the presence of MgATP. Oleoyl CoA, in the absence of MgATP, also inhibited AGP acetylation. These results suggested that MgATP supported the conversion of nuclear free fatty acids to fatty acyl CoA. Fatty acyl CoA may directly inhibit nuclear AGP acetyltransferase, but inhibition brought about by MgATP was competitive for the AGP substrate, suggesting an inhibitor close in structure to AGP. 1-Hexadecyl-2-arachidonoyl-sn-glycero-3-phosphate was identified as a competitive inhibitor for AGP in the acetylation reaction. Neuronal nuclei can convert AGP to 1-alkyl-2-acyl-sn-glycero-3-phosphate (AAcylGP), a reaction dependent upon MgATP and the presence of acetyl CoA or free CoA. This nuclear acylation was increased by free fatty acid addition and was seen using oleoyl CoA in the absence of MgATP. Nuclear AAcylGP formation was inhibited by bovine serum albumin and by Triacsin C. Thus, nuclear AGP acetyltransferase may be regulated by AGP acyltransferase activity and the availability of MgATP, a nucleotide that is rapidly lost during brain ischemia.
Roy Baker
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Department of Biochemistry, University of Toronto, Room 5202, Medical Sciences Building, 1 King's College Circle, M5S 1A8, Toronto, Ontario, Canada. roy.baker@utoronto.ca
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D000123:Acetyltransferases / Q000037:antagonists & inhibitors*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D003065:Coenzyme A / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000096:biosynthesis*; D011817:Rabbits
D005227:Fatty Acids; D010972:Platelet Activating Factor; D000255:Adenosine Triphosphate; D000123:Acetyltransferases; C052591:alkylglycerophosphate 2-O-acetyltransferase; D008274:Magnesium; D003065:Coenzyme A