CONTROL OF PYRUVATE AND β‐HYDROXYBUTYRATE UTILIZATION IN RAT BRAIN MITOCHONDRIA AND ITS RELEVANCE TO PHENYLKETONURIA AND MAPLE SYRUP URINE DISEASE

Abstract —The effects of the amino acids (phenylalanine, valine, leucine and isoleucine) which accumulate in phenylketonuria (PKU) and maple syrup urine disease (MSUD), and their analogue α‐keto acids (phenylpyruvate, α‐keto isovalerate, α‐keto isocaproate, α‐keto‐β‐Me valerate) have been studied on rat brain mitochondrial respiration. Both phenylpyruvate and α‐keto isocaproate specifically inhibited the oxidation of pyruvate plus malate and β‐hydroxybutyrate plus malate by rat brain mitochondria in the presence of ADP. However, no inhibitory effects of similar concentrations of phenylpyruvate or α‐keto isocaproate were observed on the isolated semipurified pyruvate or β‐hydroxybutyrate dehydrogenases from rat brain mitochondria. The transport of pyruvate and β‐hydroxybutyrate across the brain mitochondrial membrane was studied by both uptake and exchange of radioactively labelled substrates. Both these processes were inhibited by phenylpyruvate and α‐ketoisocaproate. The results are interpreted as providing evidence for both pyruvate and β‐hydroxybutyrate translocases across the brain mitochondrial membrane, and that the inhibition of these systems by phenylpyruvate and α‐keto isocaproate may be important lesions in phenylketonuria and maple syrup urine disease respectively.