title: Halo enol lactone inhibitors of chymotrypsin: burst kinetics and enantioselectivity of inactivation.
abstract: Burst kinetics in the inactivation of alpha-chymotrypsin by halo enol lactones 1 and 2 was observed. These results are consistent with a kinetic scheme that includes partitioning of the first acyl enzyme between transient inhibition and permanent inactivation. Partition ratios were estimated from the measured rates of the irreversible inactivation and the rates of deacylation of the second acyl enzyme. Halo enol lactones with a large burst resulted in small partition ratios, indicating a high potency of inactivation. We also observed enantioselectivity in the burst of inactivation such that the R enantiomer of lactone 1 showed a large burst, while the S enantiomer showed a little burst. This suggests that it is the R enantiomer whose binding is better suited for the covalent derivatization of the enzyme, or whose reactive halomethyl group is in an unfavorable position for the hydrolysis by water.
authors.affiliation: Department of Chemistry, University of Illinois, Urbana 61801.
authors.forename: D J
authors.initials: DJ
authors.lastname: Baek
authors.forename: J A
authors.initials: JA
authors.lastname: Katzenellenbogen
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002918:Chymotrypsin / Q000037:antagonists & inhibitors*; D007700:Kinetics; D007783:Lactones / Q000494:pharmacology*; D008433:Mathematics; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009842:Oligopeptides; D011480:Protease Inhibitors / Q000494:pharmacology*; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D007783:Lactones; D009842:Oligopeptides; D011480:Protease Inhibitors; D002918:Chymotrypsin