Glutamic acid decarboxylase inhibitor

Lmdgren, S. (1983) Effects of the glutamic acid decarboxylase inhibitor 3-mercaptopropionic acid on the synthesis of brain GABA m vivo and postmortally. / Neural Transm 58, 75-82... 

The precise mechanism of dimethylhydrazine toxicity is uncertain. In addition to the contact irritant effects, the acute effects of dimethylhydrazine exposure may involve the central nervous system as exemplified by tremors and convulsions (Shaffer and Wands 1973) and behavioral changes at sublethal doses (Streman et al. 1969). Back and Thomas (1963) noted that the deaths probably involve respiratory arrest and cardiovascular collapse. The central nervous system as a target is consistent with the delayed latency in response reported for dimethylhydrazine (Back and Thomas 1963). There is some evidence that 1,1-dimethylhydrazine may act as an inhibitor of glutamic acid decarboxylase, thereby adversely affecting the aminobutyric acid shunt, and could explain the latency of central-nervous-system effects (Back and Thomas 1963). Furthermore, vitamin B6 analogues that act as coenzymes in the aminobutyric acid shunt have been shown to be effective antagonists to 1,1-dimethylhydrazine toxicity (reviewed in Back and Thomas 1963). 

GABA synthesis inhibitors act on the enzymes involved in the decarboxylation and transamination of GABA. Glutamic acid decarboxylase (GAD), the first enzyme in GABA biosynthesis, is inhibited easily by carbonyl reagents such as hydrazines [e.g., hydrazinopropionic acid (4.164) or isonicotinic acid hydrazide (4.165)], which trap pyridoxal, the essential cofactor of the enzyme. A more specific inhibitor is allylglycine (4.166). All of these compounds cause seizures and convulsions because they decrease the concentration of GABA. 

Glutamic acid decarboxylase was assayed in a final volume of 100 / L containing 40 /tL of 200 mAf potassium phosphate buffer (pH 6.8), 10 / L of 5 mM L-glutamic acid, 5 / L of 0.2 mAf pyridoxal 5 -phosphate, 40 /tL of homogenate (2 mg protein/mL), and 1 fig of gabaquline (inhibitor of y-aminobutyric acid degradation). The reaction was stopped by the addition of 10 fiL of 100% trichloroacetic acid. After centrifugation, 5 fiL of standard 8-aminovaleric acid solution and 90 fiL of o-phthaldehyde solution (2 mg/mL 0.4 M borate buffer, pH 10.4) was added and the mixture was allowed to react for 3 to 5 minutes before injection of 20 fiL into the HPLC system. The reaction was linear for 20 minutes. 

Among the numerous enzymes that utilize pyridoxal phosphate (PLP) as cofactor, the amino acid racemases, amino acid decarboxylases (e.g., aromatic amino acids, ornithine, glutamic acid), aminotransferases (y-aminobutyrate transaminase), and a-oxamine synthases, have been the main targets in the search for fluorinated mechanism-based inhibitors. Pharmaceutical companies have played a very active role in this promising research (control of the metabolism of amino acids and neuroamines is very important at the physiological level). 

Glutamate in the brain and central nervous system can be converted to gamma amino butyric acid (GABA), which is catalyzed by glutamate decarboxylase. GABA is a neurotransmitter inhibitor compound that can be metabolized by transamination followed by oxidation. 

C5H,N02. Mr 115.13, mp. ca. 196°C, [a]l -33.7° (H2O). Non-proteinogenic amino acid in the fruit bodies of Amanita pseudoporphyria and A. abrupta. Synthetic A. is long known as an antimetabolite against Escherichia coli and Saccharomyces cerevisiae and as an inhibitor of glutamate decarboxylase (EC 4.1.1.15). Ninhydrin reaction brown. A. inhibits protein synthesis. The 4-chloro derivative of A. [2-amino-4-chloro-4-pentenoic acid, (2S)-form CsHgClNOj, Mr 149.58] is a major constituent of the free amino acids in fruit bodies of Amanita pseudoporphyria. It has antibacterial activity. 

Pharmacological evidence was obtained several years ago that indicated that tryptophan is decarboxylated to tryptamine by both animal and bacterial enzymes. More recent studies have failed to detect this reaction, but instead have shown decarboxylation to occur only after oxidation of the indole nucleus to yield 5-hydroxytryptophan. Decarboxylation of 5-hydroxytryptophan produces 5-hydroxytryptamine, serotonin, which has important, though incompletely defined functions in animal physiology. In some animal livers there is an enzyme that decarboxylates cysteic acid to taurine. Glutamic decarboxylase has been found in animal brain, where it is responsible for the formation of 7-aminobutyric acid. This product has been implicated in nervous function as an inhibitor of synaptic transmission. ... 

Preparation of a-acetylenic derivatives of a-amine acids, which are usefixl as central nervous system stimulants, antibacterial agents, and irreversible inhibitors of glutamate decarboxylase [93]. 

---