α-Cyanoamino acids and related nitriles as inhibitors of glutamate decarboxylase

Abstract

l-γ-Cyano-γ-aminobutyric acid, l-β-cyano-β-alanine, and α-cyanoglycine, new synthetic amino acids with the unique α-cyanoamino acid structure, have been found to be strongly inhibitory to Escherichia coli glutamate decarboxylase ( l-glutamate i-carboxy-lyase, EC 4.1.1.15). Eleven related nitriles of simpler structure also are active, which suggests organic nitriles as a new class of enzyme inhibitors. γ-Cyano-γ-aminobutyric acid, β-cyano-β-alanine, β-cyanopropionate and α-aminoacetonitrile have K i values of 0.014, 0.082, 3.2 and 6.2 mM, respectively. The inhibition by each is competitive with glutamic acid. The inhibition by n-butyronitrile is non-competitive with the substrate but is reversible with pyridoxal 5′-phosphate. The structurally related l-isoglutamine, glutaric and succinic acids are moderately inhibitory. Administered to chicks at a dosage near 12 mg/100 g, n-butynotrile is sedative. At a dosage of 8 mg, γ-cyano-γ-aminobutyric acid is convulsant and lethal.