Selective inhibition of gamma-aminobutyric acid aminotransferase by (3R,4R),(3S,4S)- and (3R,4S),(3S,4R)-4-amino-5-fluoro-3-phenylpentanoic acids.
(3R,4R),(3S,4S)- and (3R,4S),(3S,4R)-4-amino-5-fluoro-3-phenylpentanoic acid (1a and 1b) were synthesized and studied as selective inactivators of gamma-aminobutyric acid (GABA) aminotransferase. Neither compound caused time-dependent inactivation of the enzyme. Neither compound underwent enzyme-catalyzed transamination nor was fluoride ion eliminated from either compound by the enzyme. No 3-phenyllevulinic acid, the product of elimination of HF followed by enamine hydrolysis, was detected. However, both 1a and 1b were competitive reversible inhibitors of GABA aminotransferase; the Ki for 1a was smaller than the Km for GABA. These results suggest that 1a and 1b bind to the active site of GABA aminotransferase, but gamma-proton removal does not occur. Whereas (S)-4-amino-5-fluoropentanoic acid (AFPA) is a potent inhibitor of L-glutamic acid decarboxylase (GAD), neither 1a nor 1b at concentrations 40 times the Ki of AFPA caused any detectable competitive inhibition of GAD. Therefore, the incorporation of a phenyl substituent at the 3-position of AFPA confirms selective inhibition of GABA aminotransferase over GAD.
Silverman
R B
RB
Department of Chemistry, Northwestern University, Evanston, Illinois 60208-3113.
Nanavati
S M
SM
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors*; D000596:Amino Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D005968:Glutamate Decarboxylase / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013552:Swine
D000596:Amino Acids; C063275:4-amino-5-fluoro-3-phenylpentanoic acid; D000612:4-Aminobutyrate Transaminase; D005968:Glutamate Decarboxylase