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.

Citation

M Ito, Y Ikeda, J G Arnez, G Finocchiaro, K Tanaka. The enzymatic basis for the metabolism and inhibitory effects of valproic acid: dehydrogenation of valproyl-CoA by 2-methyl-branched-chain acyl-CoA dehydrogenase. Biochimica et biophysica acta. 1990 May 16;1034(2):213-8

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PMID: 2112956

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