Details of Grant 

EPSRC Reference:	GR/N08865/01
Title:	COMBINING THEORY AND EXPERIMENT TO EXAMINE THE MECHANISM OF CATALYSIS BY ASADH
Principal Investigator:	Hadfield, Dr A
Other Investigators:	Mulholland, Professor AJ
Researcher Co-Investigators:
Project Partners:
Department:	Biochemistry
Organisation:	University of Bristol
Scheme:	Standard Research (Pre-FEC)
Starts:	01 October 2000	Ends:	30 September 2003	Value (£):	63,257
EPSRC Research Topic Classifications:	Catalysis & enzymology Chemical Biology
EPSRC Industrial Sector Classifications:	Chemicals Pharmaceuticals and Biotechnology No relevance to Underpinning Sectors
Related Grants:
Panel History:
Summary on Grant Application Form
Enzymes are generally remarkably efficient and specific catalysts, and are finding increasingly wide use in practical synthetic and biotechnological applications. Achieving deeper understanding of the chemical principles underlying enzyme catalysis is a problem of great fundamental and practical importance. Detailed, molecular level, analysis requires identification of intermediates, transition states, catalytic residues, and the contributions of individual groups to catalysis. Here, kinetic, crystallographic and simulation methods will be combined to investigate the mechanisms of aspartate semialdehyde dehydrogenase (ASADH). ASADH, a bacterial biosynthetic enzyme, is a potential target for new antimicrobials, and a member of the important class of dehydrogenases. Crystallographic analysis has provided structures of enzyme complexes that will be the starting point for calculations. QM/MM simulations of the reaction mechanism will test mechanistic possibilities and identify important residues. Calculated rates will be compared with results of kinetic investigations, and mechanistic predictions will be tested by similar studies of mutant enzymes and alternative substrates. Classical molecular dynamics simulations will be used to investigate binding interactions and determinants of substrate specificity. This combination of techniques will improve our overall understanding of the detailed mechanism of catalysis in this widespread family of enzymes, facilitating the design of highly specific protein catalysts and inhibitors.
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Organisation Website:	http://www.bris.ac.uk