Pyruvate metabolism by homogenates of human brain: effects of phenylpyruvate and implications for the etiology of the mental retardation in phenylketonuria.

Abstract

Abstract— The effect of phenylalanine and phenylpyruvate on the metabolism of pyruvate by homogenates of human brain was investigated. In the presence of 5 mM pyruvate as substrate homogenates of human cerebral cortex fixed about 1 μmol of H14CO3‐‐ per g of tissue in 30 min. Phenylpyruvate at a concentration of 5 raw inhibited the fixation of H14 CO3‐‐ by homogenates of human brain by approximately 50 per cent, whereas 5 mM phenylalanine had no effect. The inhibition of pyruvate carboxylation by phenylpyruvate was dependent upon the concentration of the inhibitor. The activity of pyruvate carboxylase (EC 6.4.1.1) in human cerebral cortex was 02–0.4 units, with a Km for pyruvate of about 0.2 mM. Homogenates of human cerebral cortex decarboxylated [1‐14C]pyruvate to 14CO2 at a rate of about 5 μmol per g of tissue per 15 min, with a 20–50 per cent reduction in the presence of 5 mM phenylpyruvate; phenylalanine at the same concentration had no effect. The possible toxic effect of phenylpyruvate on the metabolism of pyruvate in the brains of untreated phenylketonuric patients is discussed.