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The chemistry and biophysics of phosphoryl transfer enzymes


Project Description

One of the most remarkable features of the chemistry of living organisms is the evolutionary utilisation of phosphate esters to provide biopolymers that encode genetic information, deliver temporal protein regulation, generate and distribute free energy throughout the cell, and to provide a ubiquitous handle for metabolic intermediates. The solution to the paradox between the remarkable chemical stability of phosphate esters and their facile manipulation lies in the catalytic power of enzymes to make and break P–O–C and P–O–P bonds rapidly, giving some of the largest enzymatic rate accelerations yet identified. We have made extensive use of metal fluoride complexes of archetypal enzymes to unravel how this remarkable level of catalysis is achieved. These studies have established the dominant role played by charge in catalysis by these enzymes, and it is its interplay with protein conformation that we intend to expand upon in the proposed study. Using a combination of structural biology and computational chemistry, we will elucidate how various phosphoryl transfer enzymes achieve catalysis. The study will make extensive use of heteronuclear NMR, X-ray crystallography, and MD simulations, coupled with cutting-edge theory to calculate rigorous atomic charges from first principle electron densities, as well as characterising bonding patterns and non-covalent interactions.

Contact for further Information

https://www.research.manchester.ac.uk/portal/j.waltho.html

Funding Notes

Applications are invited from self-funded students. For UK/EU tuition fees are £15,500 and International are £30,500 for 2019/20 academic year.

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or the overseas equivalent) in a related area, normally Chemistry or Biochemistry. Candidates with experience in structural biology or with an interest in enzyme activity are encouraged to apply.

References

• Griffin JL, Bowler MW, Baxter NJ, Leigh KN, Dannatt HRW, Hounslow AM, Blackburn GM, Webster CE, Cliff MJ, Waltho JP. (2012) Proc Nat Acad Sci USA 109 6910-5
• Jin Y, Bhattasali D, Pellegrini E, Forget SM, Baxter NJ, Cliff MJ, Bowler MW, Jakeman DL, Blackburn GM, Waltho JP. (2014) Proc Nat Acad Sci USA 111 12384-9
• Jin Y, Molt RW Jr, Pellegrini E, Cliff MJ, Bowler MW, Richards NG, Blackburn GM, Waltho JP. (2017) Angew Chem Int Ed Engl 56 9732-5
• Jin Y, Richards NG, Waltho JP, Blackburn GM Angew Chem Int Ed Engl. (2017) 56 4110-28
• Johnson LA, Robertson AJ, Baxter NJ, Trevitt CR, Bisson C, Jin Y, Wood HP, Hounslow

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