Award details

Mannosidase catalysis and transition-state mimicry

Reference	BBS/B/05974
Principal Investigator / Supervisor	Professor Gideon Davies
Co-Investigators / Co-Supervisors
Institution	University of York
Department	Chemistry
Funding type	Research
Value (£)	222,214
Status	Completed
Type	Research Grant
Start date	01/07/2004
End date	31/12/2007
Duration	42 months

Abstract

The enzymatic hydrolysis of glycosides is notable for the large rate enhancements, of around 10 to the power of 17-fold, reflecting exceedingly tight-binding of the transition-state. Mannosyl transfer is especially significant, both given the difficulty of non-enzymatic mannoside chemistry and the therapeutic potential of mannosidase inhibitors. We propose to study the mechanism of mannoside hydrolysis through X-ray analyses of a unique mannosidase along the reaction coordinate and to contrast this with glucoside hydrolysis by related enzymes. In addition, Linear free energy analysis (correlating Ki with log kcat/KM for a series of variants) of a substantial library of mannosidase inhibitors, in harness with 3-D structure, will probe the nature of the enzymatic transition-state yielding quantitative insight into transition-state mimicry and informing strategies for therapeutic intervention. (Joint with BBS/B/13349).

Summary

unavailable

Committee	Closed Committee - Biomolecular Sciences (BMS)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

Associated awards:

BBS/B/13349 Mannosidase catalysis and transition-state mimicry

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