title: (+/-)-(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.
authors.affiliation: Department of Chemistry, Center for Drug Discovery and Chemical Biology, Northwestern University, Evanston, Illinois 60208-3113, USA.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Wang
authors.forename: Hai
authors.initials: H
authors.lastname: Yuan
authors.forename: Dejan
authors.initials: D
authors.lastname: Nikolic
authors.forename: Richard B
authors.initials: RB
authors.lastname: Van Breemen
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
mesh_terms: D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000598:Amino Acids, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005461:Fluorine / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: C516156:5-amino-2-fluorocyclohex-3-enecarboxylic acid; D000598:Amino Acids, Cyclic; D003509:Cyclohexanecarboxylic Acids; D004791:Enzyme Inhibitors; D005461:Fluorine; D005680:gamma-Aminobutyric Acid; D000612:4-Aminobutyrate Transaminase