Inactivation of γ-Aminobutyric Acid Aminotransferase by (S,E)-4-Amino-5-fluoropent-2-enoic Acid and Effect on the Enzyme of (E)-3-(1-Aminocyclopropyl)-2-propenoic Acid

Article abstract of DOI:10.1021/jm00160a007

(S,E)-4-Amino-5-fluoropent-2-enoic acid (6) is synthesized in six steps starting from the known γ-aminobutyric acid aminotransferase (γ-Abu-T) inactivator, (S)-4-amino-5-fluoropentanoic acid (1).Compound 6 is a mechanism-based inactivator of γ-Abu-T: time-dependent inactivation is saturable and protected by substrate; thiols do not protect the enzyme from inactivation; no enzyme activity returns upon dialysis.This compound (6) binds 50 times more tightly to γ-Abu-T than does the saturated analogue (1).No transamination of 6 occurs prior to inactivation.However, five molecules of 6 are required to inactivate the enzyme with concomitant release of five fluoride ions.Therefore, four molecules are being converted to product for each inactivation event. (E)-3-(1-Aminocyclopropyl)-2-propenoic acid is synthesized in seven steps from 1-aminocyclopropanecarboxylic acid.It is prepared as a cyclopropyl derivative of the proposed intermediate in the inactivation of γ-Abu-T by 6.The cyclopropyl derivative, however, is a noncompetitive inhibitor and does not inactivate the enzyme.This study shows the usefulness and hazards of incorporation of a trans double bond into potential γ-Abu-T inactivators.