Effect of phenylalanine metabolites on the activities of enzymes of ketone body utilization in brain of suckling rats

Abstract

The effects of phenylalanine and its metabolites (phenylacetate, phenethylamine, phenyl lactate, o hydroxyphenylacetate and phenylpyruvate) on the activity of 3 hydroxybutyrate dehydrogenase (EC 1.1.1.30), 3 oxo acid CoA transferase (EC 2.8.3.5) and acetoacetyl CoA thiolase (EC 2.3.1.9) in brain of suckling rats were investigated. The 3 hydroxybutyrate dehydrogenase from the brain of suckling rats had a K(m) for 3 hydroxybutyrate of 1.2mM. Phenylpyruvate, phenylacetate and o hydroxyphenylacetate inhibited the enzyme activity with K(i) values of 0.5, 1.3 and 4.7mM respectively. The suckling rat brain 3 oxo acid CoA transferase activity had a K(m) for acetoacetate of 0.665mM and for succinyl (3 carboxypropionyl) CoA of 0.038mM. The enzyme was inhibited with respect to acetoacetate by phenylpyruvate (K(i) = 1.3mM) and o hydroxyphenylacetate (K(i) = 4.5mM). The reaction in the direction of acetoacetate was also inhibited by phenylpyruvate (K(i) = 1.6mM) and o hydroxyphenylacetate (K(i) = 4.5mM). Phenylpyruvate inhibited with respect to acetoacetyl CoA both the mitochondrial (K(i) = 3.2mM) and cytoplasmic (K(i) = 5.2mM) acetoacetyl CoA thiolase activities. The results suggest that inhibition of 3 hydroxybutyrate dehydrogenase and 3 oxo acid CoA transferase activities may impair ketone body utilization and hence lipid synthesis in the developing brain. This suggestion is discussed with reference to the pathogenesis of mental retardation in phenylketonuria.