7-Aminobutyric acid transaminase

The proposed mechanism of inactivation is depicted in Figure 13. It is reminiscent of that proposed for the inactivation of 7 aminobutyric acid transaminase by gabaculine or cycloserine. ... 

Jaeken J, Casaer P, de Cock P, Corbeel L, Eeckels R, Eggermont E, Schechter PJ, Brucher JM (1984) Gamma-aminobutyric acid-transaminase deficiency a newly recognized inborn error of neurotransmitter metabolism. Neuropediatrics 15 165-169... 

Figure 5. Inhibition of y-aminobutyric acid transaminase by 4-aminohex-5-ynoic acid (y-acetylenic GABA)...

Cassel, G., Karlsson, L., Sellstrom, A. (1991). On the inhibition of glutamic acid decarboxylase and gamma-aminobutyric acid transaminase by sodium cyanide. P/iarmaco/. Toxicol. 69 238-41. 

Lin C-T, Li J-Z, Wu J-Y (1983) Immunocytochemical localization of L-glutamate decarboxylase, gamma-aminobutyric acid transaminase, cysteine sulfinic acid decarboxylase, aspartate aminotransferase and somatostatin in rat retina. Brain Res 270 273-283. 

In this chapter, we discuss the synthetic methodologies used to prepare fluoroolefins and present examples of mechanism-based inhibitors of amine oxidases, r-aminobutyric acid transaminase and S-adenosylhomocysteine hydrolase which incorporate this structural functionality. Ve have restricted our discussion to the syntheses of terminal mono-, di- and trifluoroolefins, omitting the large body of synthetic endeavour directed towards other fluoro olefins (4). 

After the initial discovery that 0-fluoromethylene-substituted amines (e.g., 184, Table 1) were potent, mechanism-based inhibitors of monoamine oxidase (MAO) (41), the concept was successfully broadened to include most of the common amine oxidases (Table 1). This approach was also used to design inhibitors of y-aminobutyric acid transaminase both the a- and 0- substituted amino acids 189 and 190 were found to inactivate this enzyme. Recently, applica-tion of this concept to the design of inhibitors of S-adenosyl-homocysteine hydrolase (SAH) has led to the discovery of very potent inhibitors of this enzyme (e.g., 176, Table 1). 

Succinic semialdehyde (SSA) is synthesized in the mitochondria through transamination of y-aminobutyric acid (GABA) by GABA transaminase (GABA-T). Most of the SSA is oxidized by SSA dehydrogenase (SSA-DH) to form succinate, which is used for energy metabolism and results in the end products CO2 + H2O, which are expired. A small portion of SSA (<2%) is converted by SSA reductase (SSA-R) in the cytosol to GHB. GHB may also be oxidized back to SSA by GHB dehydrogenase (GHB-DH). 

This enzyme [EC 2.6.1.21], also known as D-aspartate aminotransferase, D-amino acid aminotransferase, and D-amino acid transaminase, catalyzes the reversible pyridoxal-phosphate-dependent reaction of D-alanine with a-ketoglutarate to yield pyruvate and D-glutamate. The enzyme will also utilize as substrates the D-stereoisomers of leucine, aspartate, glutamate, aminobutyrate, norva-hne, and asparagine. See o-Amino Acid Aminotransferase... 

Schor DS, Struys EA, Hogema BM, Gibson KM, Jakobs C (2001) Development of a stable-isotope dilution assay for gamma-aminobutyric acid (GABA) transaminase in isolated leukocytes and evidence that GABA and beta-alanine transaminases are identical. Clin Chem 47 525-531... 

Silverman and associates explored a variety of potential inactivators for GABA [y-aminobutyric acid, H3T (CH2)3COOH] transaminase, another pyridoxal-dependent enzyme. In the reaction of the enzyme with 4-amino-5-fluoropentanoic acid, Silverman and Invergo wrote the mechanism in equation 25 for the covalent interaction of the enzyme with the inactivator161. The mechanism, dubbed the enamine mechanism, was earlier suggested by Metzler s group162, who had also proposed, as a test, alkaline treatment of the inactivated enzyme that would result in the release of the coenzyme-bound modified inactivator. 

GABA aminotransferase (GABA transaminase, GABA-T) catalyzes the conversion of y-aminobutyric acid to succinic semialdehyde with the subsequent transfer of an amino group to pyruvate (Equation 17.52). 

Figure 6.5. Major pathway for the synthesis and degradation of GABA GABA y-aminobutyric acid GAD, glutamic acid decarboxylase GABA-T, GABA transaminase.

Examples of uimatural L-amino acids that can be accessed by transaminase methodology are L-2-aminobutyric acid, i.-homophcnylalaninc, and L-lert-leu-cine the latter is not accessible by an asymmetric hydrogenation approach because of the absence of a P-hydrogen. 

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