The enzymatic basis for the metabolism and inhibitory effects of valproic acid: dehydrogenation of valproyl-CoA by 2-methyl-branched-chain acyl-CoA dehydrogenase.
Five distinct acyl-CoA dehydrogenases are currently known. These are short, medium, long and 2-methyl-branched-chain acyl-CoA dehydrogenases, and isovaleryl-CoA dehydrogenase. We tested these five acyl-CoA dehydrogenases for their ability to dehydrogenate valproyl-CoA using pure enzyme preparations isolated from rat liver mitochondria. The activities of the pure human short-chain, medium-chain and isovaleryl enzymes purified from post-mortem livers, and a long-chain acyl-CoA dehydrogenase preparation partially purified from placental mitochondria, were also tested. Valproyl-CoA was dehydrogenated at a significant rate (0.167 mumol/min per mg protein) only by rat 2-methyl-branched-chain acyl-CoA dehydrogenase. Human 2-methyl-branched-chain acyl-CoA dehydrogenase has not been purified; therefore, it could not be tested. Since four other human acyl-CoA dehydrogenases did not dehydrogenate isobutyryl-CoA, 2-methylbutyryl-CoA (obligatory intermediates from valine and isoleucine, respectively) nor valproyl-CoA, it is reasonable to assume that valproyl-CoA is dehydrogenated by 2-methyl-branch-chain acyl-CoA dehydrogenase in man as well. We identified 2-propyl-2-pentenoyl-CoA as the reaction product from valproyl-CoA by mass spectral analysis of the acyl moiety. Valproyl-CoA, at 0.3 mM, moderately inhibited human acyl-CoA dehydrogenases with the exception of the long-chain enzyme. 5 mM free valproic acid inhibited the activities of various acyl-CoA dehydrogenases only very weakly.
Ito
M
M
Yale University School of Medicine, Department of Human Genetics, New Haven, CT.
Ikeda
Y
Y
Arnez
J G
JG
Finocchiaro
G
G
Tanaka
K
K
D000214:Acyl Coenzyme A / Q000378:metabolism* / Q000494:pharmacology; D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000378:metabolism; D000818:Animals; D002849:Chromatography, Gas; D006801:Humans; D007700:Kinetics; D013058:Mass Spectrometry; D008930:Mitochondria, Liver / Q000201:enzymology; D010088:Oxidoreductases / Q000378:metabolism*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D051381:Rats; D014635:Valproic Acid / Q000378:metabolism* / Q000494:pharmacology
D000214:Acyl Coenzyme A; C045335:valproyl-coenzyme A; D014635:Valproic Acid; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; D044942:Acyl-CoA Dehydrogenase, Long-Chain; C038808:2-methylacyl-CoA dehydrogenase