Halo enol lactone and protio enol lactone inhibitors of alpha-chymotrypsin: Mechanism and stereospecific behavior of inhibition

A kinetic study of inactivation of α-chymotrypsin by enol lactones was performed. Halo enol lactones, 3-(1-naphthyl)-6(E)-(iodomethylene)tetrahydro-2-pyranone (αNp6I) and 3-phenyl-6(E)-(bromomethylene)tetrahydro-2-pyranone (αPh6Br), showed burst kinetics in the inactivation of the enzyme, which requires a complicated kinetic scheme including partitioning of the first acyl enzyme between the covalent derivatization of the enzyme by the revealed halomethyl ketone reactive group (permanent inactivation) and formation of the second acyl enzyme by the hydrolysis of the halomethyl ketone of the first acyl enzyme to the non-reactive hydroxymethyl ketone group (transient inhibition). Deacylation of the second acyl enzyme leads to reactivation to free enzyme, which will be available for inactivation again. From the rate of the time-dependent irreversible inactivation and the rate of deacylation, a partition ratio between transient inhibition and permanent inactivation was calculated. A halo enol lactone with a small partition ratio showed a large burst. The efficiency of halo enol lactones as suicide inactivators is thus limited by the hydrolysis of the halomethyl reactive group.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2011

Author dc:creator

• Baek, Du-Jong

• Chemistry, Biochemistry
• Chemistry, Organic
• Chemistry, Pharmaceutical

Statement dc:rights

• Copyright 1989 Baek, Du-Jong

Language dc:language

eng

Identifier

AAI8924762
(UMI)AAI8924762

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/22512