Propionic and
methylmalonic acidemia are both known to be associated with
hyperammonemia. Rats injected with 10 or 20 mmol/kg of
propionate or 20 mmol/kg of methylmalonate, along with 1.5 g/kg of a mixture of
amino acids, developed severe
hyperammonemia, whereas rats administered the same dosages of
acetate did not. In vitro, neither propionyl nor
methylmalonyl CoA affected the activity of
carbamyl phosphate synthetase I,
ornithine transcarbamylase, nor the activation constant (K(A)) of
carbamyl phosphate synthetase I for N-acetyl
glutamate. Furthermore, rats injected with
propionate showed no alteration of liver
amino acid concentrations, which could explain impaired ureagenesis. Animals injected with methylmalonate showed an increase in both
citrulline and
aspartate, suggesting that
argininosuccinic acid synthetase may also have been inhibited. Liver
ATP levels were unchanged. Citrullinogenesis, measured in intact mitochondria from livers of injected animals, was reduced 20-25% by 20 mmol/kg of
propionate or methylmalonate (compared with
acetate). This effect was attributable to an impairment in the normal rise of liver N-acetyl
glutamate content after
amino acid injection. Thus,
carbamyl phosphate synthetase I activation was reduced. Liver levels of
acetyl CoA and free
CoA were reduced. Levels of unidentified
acyl CoA derivatives rose, presumably reflecting the accumulation of propionyl and
methylmalonyl CoA. Thus, the principal mechanism for
hyperammonemia induced by these
acids is depletion of liver N-acetyl
glutamate, which is in turn attributable to depletion of
acetyl CoA and/or competitive inhibition by propionyl and
methylmalonyl CoA of N-acetyl
glutamate synthetase. Injection of methylmalonate may also have an additional inhibitory effect on
argininosuccinic acid synthetase.