Irreversible Inhibition of Gaba-T by Halogenated Analogues of βAlanine

Abstract

β-Difluoromethyl-β-alanine (3-amino-4,4-difluorobutanoic acid) is a potent in vitro and in vivo inhibitor of GABA-T. The rate of inhibition of GABA-T is concentration- and time-dependent. The inactivation is active-site directed. No reactive species escapes from the active site before reacting with the enzyme. The inhibition is irreversible and stereospecific. The use of β-²H-β-difluoromethyl-β-alanine results in a marked primary isotope effect in vitro and in vivo. The use of differently substituted dihalogeno derivatives of β-alanine suggests that the rate of inhibition is dependent on the nature and position of the leaving group. The mechanism of inhibition is discussed on the basis of spectral changes.

Key Words: :

• 4-Aminobutyrate metabolism
• irreversible inhibition
• 3-amino-4,4-difluorobutanoic acid
• 3-amino-4-chloro-4-fluorobutanoic acid
• 3-amino-2,4-difluorobutanoic acid