GABA-aminotransferase

In addition to a-allenic a-amino acids, the corresponding allenic derivatives of y-aminobutyric acid (GABA) have also been synthesized as potential inhibitors of the pyridoxal phosphate-dependent enzyme GABA-aminotransferase (Scheme 18.49) [131,138-142]. The synthesis of y-allenyl-GABA (152) and its methylated derivatives was accomplished through Crabbe reaction [131], aza-Cope rearrangement [138] and lactam allenylation [139], whereas the fluoroallene 153 was prepared by SN2 -reduc-tion of a propargylic chloride [141]. 

Vigabatrin (irreversible GABA aminotransferase inhibitor), zonisamide, lamotrigine (217) (glutamate inhibitor), oxcarbazepine (218), levetiracetam (219), piracetam, tiagabine (220),... 

Loscher, W. (1993) In vivo administration of valproate reduces the netve tetminal (synaptosomal) activity of GABA aminotransferase in discrete btain ateas of tats. Neurosci Lett 160 177-80. 

The answer is c. (Hardman, p 481. Katzung, pp 404-405.) Vigabatrin is useful in partial seizures. It is an irreversible inhibitor of GABA aminotransferase, an enzyme responsible for the termination of GABA action. This results in accumulation of GABA at synaptic sites, thereby enhancing its effect. 

Further fluorinated synthons 20 (equation 17)92 and 21 lead to Reformatsky intermediates which are synthetic equivalents of a formal 4,4-difluoroacetoacetate dianion and of a carbalkoxy trifluoromethyl carbene, respectively. The latter has been exploited in a synthesis of E-22 and Z-22, both inhibitors of GABA aminotransferase (equation 18)93. 

GABA analogs are used in the treatment of epilepsy and hypertension. Levels of GABA can also be increased by administering inhibitors of the GABA-degrading enzyme GABA aminotransferase. Another important neuro-transmitter, serotonin, is derived from tryptophan in a two-step pathway. 

Fig. 1.3 Reactions showing synthesis of glutamate in brain. Aspartate aminotransferase (1) glu-taminase (2) glutamate dehydrogenase (3) GABA aminotransferase (4) alanine aminotransferase (5) ornithine aminotransferase (6) Al-pyrroline 5-carboxylic acid dehydrogenase (7) and asparagine synthetase (8)...

Ethosuximide has an important effect on Ca2+ currents, reducing the low-threshold (T-type) current. This effect is seen at therapeutically relevant concentrations in thalamic neurons. The T-type calcium currents are thought to provide a pacemaker current in thalamic neurons responsible for generating the rhythmic cortical discharge of an absence attack. Inhibition of this current could therefore account for the specific therapeutic action of ethosuximide. Ethosuximide also inhibits Na+/K+ ATPase, depresses the cerebral metabolic rate, and inhibits GABA aminotransferase. However, none of these actions are seen at therapeutic concentrations. 

Glutamate decarboxylase and GABA aminotransferase are found in regions of the central nervous system other than those in which GABA has a... 

Figure 6.3. GABA shunt as an alternative to a-ketoglutarate dehydrogenase in the citric acid cycle. 2-Oxoglutarate dehydrogenase, EC 1.2.4.2 glutamate decarboxylase, EC 4.1.1.15 GABA aminotransferase, EC 2.6.1.19 and succinic semialdehyde dehydrogenase, ECl.2.1.16.

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). 

The commercially available lactam 76 is usable for amino acid synthesis as a chiral cyclic building block. 4-Fluoro- and 4,4-difluoro-3-aminocyclopentane carboxylic acids 79 and 81, potential inhibitors of y-aminobutanoic acid (GABA) aminotransferase, were synthesized as shown in Scheme 9.19 [39]. In this process, replacement of hydroxyl or carbonyl groups with fluorine was achieved by the use of DAST. Interestingly, the stereochemistry in substitution with DAST is retained [40], although it is by inversion in most cases [26]. Hydrolysis of 78 gave 80. 

Fig. 9. Three-dimensional structure of dopa decarboxylase with the drug carbidopa covalently bound to PLP (106) (a), and GABA aminotransferase with the drug vigabatrin covalently bound to PLP (107) (b).

Figure 22 Schematic example of the arginine switch in GABA aminotransferase.

DAPA aminotransferase dNTP-hexose aminotransferase GSA aminotransferase GABA aminotransferase Lys -aminotransferase 2,5-diaminobutyrate aminotr. 

Fig. 11. Steric course of aminotransferases acting on an w-aminomethylene group of enantiomeric [4- H]GABA. (i) =

C7H9NO2, Mr 139.15, amorphous powder, [a]u-454° (H2O). Synthetic racemate, mp. 196-197 °C antibiotic from Streptomyces toyocaensis, G. inhibits the enzyme GABA aminotransferase by formation of a Schiff s base and subsequent (irreversible) aromatiza-tion with formation of a m-anthranilic acid derivative. For racemic synthesis, see Lit, asymmetric or regio-selective syntheses, see... 

Wu J -Y (1976) Purification and properties of L-glutamate decarboxylase (GAD) and GABA-aminotransferase (GABA-T), in GABA m Nervous System Function (Roberts E, Chase T. and Tower D., eds.), pp 7-55. Raven Press, New York, N Y. 

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