Reversed hydroxamate-bearing thermolysin inhibitors mimic a high-energy intermediate along the enzyme-catalyzed proteolytic reaction pathway.
A series of inhibitors that bear a reversed hydroxamate moiety have been evaluated as transition state analogue inhibitors for thermolysin. A linear correlation is observed between the K(i) values of these inhibitors and the kinetic parameters (K(M)/k(cat)) of the parallel series of related substrates, satisfying the criterion stipulated for transition state analogue inhibitors by Bartlett and Marlowe. Furthermore, examination of the binding mode of a related reversed hydroxamate bearing thermolysin inhibitor, in comparison with a transition state postulated for the enzyme-catalyzed proteolytic reaction revealed that the inhibitors under study mimic the electronic as well as the geometric characteristics of the transition state. On the basis of these results it may be concluded that the hydroxamate-bearing zinc protease inhibitors are a new type of transition state analogue inhibitors.
Park
Jung Dae
JD
Center for Integrated Molecular Systems, Division of Molecular and Life Sciences, Pohang University of Science and Technology, San 31 Hyojadong, Pohang 790-784, South Korea.
Kim
Dong H
DH
D002384:Catalysis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000494:pharmacology; D018716:Molecular Mimicry; D010447:Peptide Hydrolases / Q000378:metabolism; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013820:Thermolysin / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D010447:Peptide Hydrolases; D013820:Thermolysin