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CV
Professor Waltho trained with Dudley Williams in the University Chemical Laboratory at Cambridge, Andy Vinter at SmithKline French, and Peter Wright at the Scripps Research Institute, before taking up post in 1990 as a Lecturer in the Department of Molecular Biology & Biotechnology at the University of Sheffield. He is now the Gibson Professor of Biophysics in this department. Since 2008, Professor Waltho has also held the position of Professor of NMR spectroscopy in the Manchester Institute of Biotechnology at the University of Manchester, where he runs the high field Biomolecular NMR Facility. His research has addressed questions relating to non-covalent molecular interactions, focusing on protein structure, protein folding, and protein misfolding into amyloid states. Recently the attention of the laboratory has turned to understanding the fundamentals of enzyme catalysis, with a particular interest in phosphoryl group and hydride transfer reactions.
Abstract
Using a combination of multinuclear NMR spectroscopy, high resolution X-ray crystallography and computational chemistry we are able to examine the conformational behaviour of proteins under a very wide range of conditions. Recently, we have focused on enzymes that catalyse the transfer of phosphoryl groups, where the non-catalysed reactions can be among the slowest known for a physiological process: phosphate monoesters, for example, have calculated lifetimes to spontaneous hydrolysis of up to 1012 years. I will use a range of phosphoryl transfer enzymes to illustrate what contributes to the very high levels of catalysis achieved by these enzymes. Specifically, we have examined what happens during domain folding, during assembly of the native enzyme, during substrate binding, and during transition state binding. The introduction of metal fluoride species to mimic the ground state and the transition state of the transferring phosphate group has allowed us to dissect the steps involved in catalysis. In particular, these enzymes illustrate how the charge distribution in the close vicinity of the transferring phosphate is tightly controlled by the enzyme, and how the near transition state complex conformation reacts to modulation of these charges. I will also discuss phosphoryl transfer in the context of the domain closure required to bring about catalysis.
Some relevant publications
Baxter N J et al (2008), J Am Chem Soc, 130: 3952-3958
Cliff M Jet al (2010), J Am Chem Soc, 132: 6507-6516
Marston J P et al (2010), J Mol Biol, 396: 345-360
Baxter N J et al (2010), Proc Nat Acad Sci USA, 107: 4555-4560
Liu X et al (2011), J Am Chem Soc, 133: 3989-3994 |
