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BBSRC Grant: Protein-ligand coupled motions in DHFR catalysis

27 January 2012

Enzymes are efficient catalysts that can achieve rate enhancements of up to 21 orders of magnitude relative to the uncatalysed reactions. However, despite many decades of experimentation, the precise causes of these remarkable rate enhancements are not fully understood.

A £550k grant has just been awarded by BBSRC to staff in the School of Chemistry. The award, entitled “Protein-ligand coupled motions in DHFR catalysis” was awarded to Professor Rudolf Allemann and Professor Gerald Richter in the School of Chemistry in collaboration with Dr Matthew Crump in the School of Chemistry at Bristol University.

Hydrogen transfer reactions are of fundamental importance in all biological processes. In order to understand the effects that control the speed of these reactions, motions in the enzyme-substrate complex must be taken into account. The role that enzyme motions play in the physical steps of the catalysed reaction (i.e. binding of substrates, release of products and global conformational changes) is well established. However, the influence of such dynamic motions on the actual chemistry of an enzyme-catalysed reaction is less well defined. In particular, the influence of fast motions that actively promote the reaction is a current hot topic in mechanistic enzyme catalysis.

The correlation between dynamics and enzymatic chemistry will be examined using the enzyme dihydrofolate reductase. This enzyme is required in many essential biochemical processes including the synthesis of DNA and amino acids. It is therefore a long established drug target and several inhibitors have been discovered and successfully developed as antibacterial, antimalarial and anti-tumour drugs. The increasing and inherently unavoidable problem of drug resistance together with the poor yield from screening programmes demands a rational approach to develop new inhibitors based on a thorough understanding of the mechanistic and dynamic details of the catalytic process.