The Formation of Ketone Bodies From Isovaleric Acid

In the course of investigations on the biosynthesis of cholesterol, a number of compounds which contained deuterium as a marker were tested as precursors for the steroid structure (1, 2).Aside from acetic acid, which is an efficient precursor (3), two substances, leucine and isovaleric acid, gave rise to high deuterium concentrations in cholesterol (4).Special significance was attached to this finding because these compounds, like cholesterol, contain branched chains.Since leucine and isovaleric acid are ketogenic (5,6) and also form acetyl groups (4), it was not clear whether the conversion of these compounds to steroids is direct or attributable to the intermediary formation of 2-carbon fragments.The finding that deuterioisovaleric acid and deuterioleucine gave identical isotope concentrations in cholesterol and N-acetyl groups suggested that isovaleric acid is an intermediate in leucine metabolism (4).Either substance might therefore be used in a study of the fate of these branched chain compounds.It was felt that information on the conversion of these compounds to ketone bodies in vitro might be of aid in interpreting their rale in steroid synthesis.Isovaleric acid appeared to be a more suitable substrate than leucine since it is oxidized more rapidly in liver slices (7).Isovaleric acid was synthesized to contain Cl3 in the methyl groups and Cl4 in the carboxyl group.The compound was incubated with rat liver slices and the isotope concentrations of the ketone bodies were determined.EXPERIMENTAL Preparation of Labeled Compounds 4,4'-C13-Isovaleric acid was synthesized by the following series of reactions: