title: Slow-binding inhibition: the general case.
abstract: Two basic kinetic mechanisms have been described to account for the slow-binding inhibition of enzyme-catalyzed reactions. One mechanism involves the slow interaction of an inhibitor with enzyme (Mechanism A), while the other involves the rapid formation of an enzyme-inhibitor complex that undergoes a slow isomerization reaction (Mechanism B). But the initial interaction of enzyme and inhibitor may not necessarily be fast so that the free enzyme and the two forms of enzyme inhibitor complex are in steady-state equilibrium. This assumption would give rise to a more general form of Mechanism B. The present study has been concerned with attempts to determine whether it might be possible to distinguish between the three possible inhibition mechanisms by steady-state kinetic techniques. The approach to the investigation has been to derive theoretical data for the most general mechanism by using three different ratios for the two rate constants that determine which mechanism applies. The progress curve data were then fitted to the rate equations that describe the other two mechanisms. The results draw attention to the difficulties of deducing that experimental data conform to the most general mechanism. They also show how the values for the kinetic parameters, as determined from fits of the data to the equations that describe Mechanisms A and B, can be considerably in error.
authors.affiliation: Division of Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Sculley
authors.forename: J F
authors.initials: JF
authors.lastname: Morrison
authors.forename: W W
authors.initials: WW
authors.lastname: Cleland
mesh_terms: D055598:Chemical Phenomena; D002621:Chemistry; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D007700:Kinetics; D008956:Models, Chemical; D011485:Protein Binding
chemical_list: D004791:Enzyme Inhibitors