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Structural and biochemical evidence for a boat-like transition state in β-mannosidases
- Source :
- Nature Chemical Biology. 4:306-312
- Publication Year :
- 2008
- Publisher :
- Springer Science and Business Media LLC, 2008.
-
Abstract
- Enzyme inhibition through mimicry of the transition state is a major area for the design of new therapeutic agents. Emerging evidence suggests that many retaining glycosidases that are active on alpha- or beta-mannosides harness unusual B2,5 (boat) transition states. Here we present the analysis of 25 putative beta-mannosidase inhibitors, whose Ki values range from nanomolar to millimolar, on the Bacteroides thetaiotaomicron beta-mannosidase BtMan2A. B2,5 or closely related conformations were observed for all tightly binding compounds. Subsequent linear free energy relationships that correlate log Ki with log Km/kcat for a series of active center variants highlight aryl-substituted mannoimidazoles as powerful transition state mimics in which the binding energy of the aryl group enhances both binding and the degree of transition state mimicry. Support for a B2,5 transition state during enzymatic beta-mannosidase hydrolysis should also facilitate the design and exploitation of transition state mimics for the inhibition of retaining alpha-mannosidases--an area that is emerging for anticancer therapeutics.
- Subjects :
- chemistry.chemical_classification
Transition (genetics)
Protein Conformation
Chemistry
Stereochemistry
Hydrolysis
Molecular Mimicry
digestive, oral, and skin physiology
Binding energy
beta-Mannosidase
Cell Biology
Transition state
Active center
Enzyme
Hydrolase
Enzyme kinetics
Enzyme Inhibitors
Mannosidases
Molecular Biology
Subjects
Details
- ISSN :
- 15524469 and 15524450
- Volume :
- 4
- Database :
- OpenAIRE
- Journal :
- Nature Chemical Biology
- Accession number :
- edsair.doi.dedup.....c9e7f9e99a04789f2fdec770648d96cc