INHIBITION OF BRAIN GLUTAMATE DECARBOXYLASE BY 2‐KETO‐4‐PENTENOIC ACID, A METABOLITE OF ALLYLGLYCINE1

Abstract

Abstract— 2‐Keto‐4‐pentenoic acid, a potent inhibitor of brain glutamate decarboxylase (Orlowskiet al., 1977) was prepared by oxidative deamination of l‐allylglycine with snake venom l‐amino acid oxidase. In the presence of glutamate the keto acid is a competitive inhibitor of the enzyme with respect to glutamate; its Ki is 2.4 ± 10−6m. After preincubation of brain glutamate decarboxylase with 2‐keto‐4‐pentenoic acid in the absence of glutamate, a slow and incomplete reactivation is obtained by prolonged dialysis, Sephadex gel‐filtration, and dilution, suggesting the formation of a slowly dissociating enzyme‐inhibitor complex and partial inactivation of the enzyme. In vivo inhibition of brain glutamate decarboxylase after administration of allylglycine is maximal after 2‐8 h with activity returning to normal after 16 h. The inhibition of the enzyme after administration of d‐allylglycine was greatest in the cerebellum and the medulla‐pons area, the sites of the highest activity of d‐amino acid oxidase. These results are interpreted as strongly supporting the postulate that allylglycine‐induced inhibition of brain glutamate decarboxylase is due to the in vivo formation of 2‐keto‐4‐pentenoic acid.