alpha-Aminomethylglutarate, a beta-amino analog of glutamate that interacts with glutamine synthetase and the enzymes that catalyze glutathione synthesis.
The glutamate analog, alpha-aminomethylglutaric acid, was synthetized by Michael addition of ammonia to 2-methylene glutaronitrile followed by hydrolysis of the intermediate alpha-aminomethylglutaryl nitrile; the analog cyclizes readily on heating to 2-piperidone-5-carboxylic acid. Sheep brain glutamine synthetase utilizes one isomer of DL-alpha-aminomethylglutarate at about 10% of the rate with L-glutamate. gamma-Glutamylcysteine synthetase uses both isomers of DL-alpha-aminomethylglutarate, preferentially acting on the same isomer used by glutamine synthetase. gamma-(alpha-Aminomethyl)glutaryl-alpha-aminobutyrate, prepared enzymatically with gamma-glutamylcysteine synthetase, was found to be a substrate and an inhibitor of glutathione synthetase. alpha-Aminomethylglutarate does not inhibit gamma-glutamyl cyclotransferase and gamma-glutamyl transpeptidase appreciably. When alpha-aminomethylglutarate was administered to mice, there were substantial decreases in the levels of glutamine, glutathione, glutamate, and glycine in the kidney, and of glutamine and glutamate in the liver, indicating that this glutamate analog is effective as an inhibitor of glutamine and glutathione synthesis in vivo, and suggesting that it may also inhibit other enzymes.
D000596:Amino Acids / Q000032:analysis / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism*; D005977:Glutarates / Q000138:chemical synthesis* / Q000494:pharmacology; D005978:Glutathione / Q000096:biosynthesis*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008744:Methylamines / Q000138:chemical synthesis / Q000494:pharmacology; D008968:Molecular Conformation; D010453:Peptide Synthases / Q000378:metabolism; D012756:Sheep; D013329:Structure-Activity Relationship
D000596:Amino Acids; D005977:Glutarates; D008744:Methylamines; C012178:alpha-aminomethylglutarate; D005974:Glutamate-Ammonia Ligase; D010453:Peptide Synthases; D005978:Glutathione