Metabolism of methylmalonic acid in rats. Is methylmalonyl-coenzyme a racemase deficiency symptomatic in man?

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Abstract

Vitamin B12-deficient and normal rats were loaded with methylmalonic (MMA) and ethylmalonic acids labeled with 13C in the carboxyl groups and with 2H in the alkyl groups. Significant fractions of the administered acids were excreted in both the B12-deficient and the normal animal, having undergone exchange of both their 13C-labeled carboxyl groups with endogenous 12C. The exchange of the alpha-1H of MMA in 2H2O at 25 degrees C and pH 7.5 was found by 1H-nuclear magnetic resonance to have a half-life of 28.3 min. These results show that a fraction of in vivo metabolism through the propionate-to-succinate pathway occurs via a shunt involving free MMA. The enzymes of this pathway are thought to utilize only coenzyme A (CoA) esters. To allow for the exchange of the second CoA-bound carboxyl group, we propose the deacylation of the once exchanged acid with spontaneous racemization (relative to the 13C-carboxyl group), followed by reacylation, thus exposing the labeled carboxyl to decarboxylation. The significance of this mechanism involving free MMA is that racemization of methylmalonyl (MM)-CoA may also occur without the intervention of MM-CoA racemase. A deficiency of this enzyme need not result in symptomatic methylmalonic aciduria.

Authors

J A Montgomery, O A Mamer, C R Scriver