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(+/-)-(1S,2R,5S)-5-Amino-2-fluorocyclohex-3-enecarboxylic acid. A potent GABA aminotransferase inactivator that irreversibly inhibits via an elimination-aromatization pathway.

Abstract：

:Inhibition of gamma-aminobutyric acid aminotransferase (GABA-AT) increases the concentration of GABA, an inhibitory neurotransmitter in human brain, which could have therapeutic applications for a variety of neurological diseases, including epilepsy. On the basis of studies of several previously synthesized conformationally restricted GABA-AT inhibitors, (+/-)-(1S,2R,5S)-5-amino-2-fluorocyclohex-3-enecarboxylic acid (12) was designed as a mechanism-based inactivator. This compound was shown to irreversibly inhibit GABA-AT; substrate protects the enzyme from inactivation. Mechanistic experiments demonstrated the loss of one fluoride ion per active site during inactivation and the formation of N-m-carboxyphenylpyridoxamine 5'-phosphate (26), the same product generated by inactivation of GABA-AT by gabaculine (8). An elimination-aromatization mechanism is proposed to account for these results.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Wang Z,Yuan H,Nikolic D,Van Breemen RB,Silverman RB

doi

10.1021/bi061592m

subject

Has Abstract

pub_date

2006-12-05 00:00:00

pages

14513-22

issue

48

eissn

0006-2960

issn

1520-4995

journal_volume

45

pub_type

杂志文章

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