title: Structure-reactivity relationships in the inactivation of elastase by beta-sultams.
abstract: N-Acyl-beta-sultams are time dependent irreversible active site directed inhibitors of elastase. The rate of inactivation is first order with respect to beta-sultam concentration and the second order rate constants show a similar dependence on pH to that for the hydrolysis of a peptide substrate. Inactivation is due to the formation of a stable 1:1 enzyme inhibitor complex as a result of the active site serine being sulfonylated by the beta-sultam. Ring opening of the beta-sultam occurs by S-N fission in contrast to the C-N fission observed in the acylation of elastase by N-acylsulfonamides. Structure-activity effects are compared between sulfonylation of the enzyme and alkaline hydrolysis. Variation in 4-alkyl and N-substituted beta-sultams causes differences in the rates of inactivation by 4 orders of magnitude.
authors.affiliation: Department of Chemical and Biological Sciences, University of Huddersfield, Queensgate, Huddersfield, UK HD1 3DH.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Hinchliffe
authors.forename: J Matthew
authors.initials: JM
authors.lastname: Wood
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davis
authors.forename: Rupert P
authors.initials: RP
authors.lastname: Austin
authors.forename: R Paul
authors.initials: RP
authors.lastname: Beckett
authors.forename: Michael I
authors.initials: MI
authors.lastname: Page
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008958:Models, Molecular; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D010455:Peptides / Q000737:chemistry; D012694:Serine / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D010455:Peptides; D013449:Sulfonamides; C480101:beta-sultam; D012694:Serine; D010196:Pancreatic Elastase