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Transforming nitrite chemistry with semi-synthetic heme proteins (MACMILLANU16SF)

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  • Full or part time
    Dr MacMillan
  • Application Deadline
    No more applications being accepted
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

The transformation of the nitrite ion (NO2-) into nitric oxide (NO) which is both a cytotoxin and a key biological signalling molecule is of interest to both environmental and life scientists. Bacteria harbour metalloenzymes (nitrite reductases) that catalyse this reaction, which is an important step in the biogeochemical nitrogen cycle. Mammals lack a specific nitrite reductase, but under hypoxic (oxygen limiting) conditions the well-known oxygen binding pigment myoglobin will catalyse the same reaction. Although this myoglobin catalysed reaction is very slow there is some evidence that it can help protect cells and tissues against ischaemic attack (for instance a heart attack or a stroke). This project aims to modify myoglobin through a novel approach in which the environment of the nitrite binding site is modified through protein engineering and the natural cofactor, heme b, is replaced with a range of natural and synthetic metalloporphyrins that are better suited to sustaining nitrite reduction.

The development of these "semi-synthetic" heme proteins has the potential to provide new information about the chemical principals governing nitrite reduction as well as providing a range of high-value reagents for applications that include synthetic chemistry and bio-sensing as well as being candidate pharmaceuticals.

This interdisciplinary project has been designed to give the successful candidate the opportunity to work at the interface between Chemistry and Biology. They will receive extensive training in protein biochemistry, rapid reaction kinetics and the unique constellation of advanced spectroscopies that are available at UEA including Magnetic Circular Dichroism and the multi-frequency Electron Paramagnetic Resonance methods; ENDOR, ESEEM, HYSCORE and REFINE.

Funding Notes

This PhD project is offered on a self-funding basis. It is open to applicants with funding or those applying to funding sources. Details of tuition fees can be found at http://www.uea.ac.uk/pgresearch/pgrfees.

A bench fee is also payable on top of the tuition fee to cover specialist equipment or laboratory costs required for the research. The amount charged annually will vary considerably depending on the nature of the project and applicants should contact the primary supervisor for further information about the fee associated with the project.

References

i) Richardson, D.J and Watmough, N.J. Inorganic Nitrogen Metabolism in Bacteria (1999) Curr. Opin. Chem. Biol. 3: 207-219
ii) van Wonderen, J.H., Knight, C., Oganesyan, V.S., George, S.J., Zumft, W.G. and Cheesman, M.R. Activation of the Cytochrome cd1 Nitrite Reductase from Paracoccus pantotrophus: Reaction of the oxidized enzyme with substrate drives a ligand switch at heme c (2007) J. Biol. Chem. 282: 28207-28215.
iii) Brittain, T., Baker, A.R., Butler, C.S., Little, R.H., Lowe, D.J., Greenwood, C., & Watmough, N.J. The Reaction of Variant Sperm Whale Myoglobins with Hydrogen Peroxide; the effects of mutating a histidine residue in the heme distal pocket. (1997) Biochem. J. 326: 109-115
iv) Bradley, J.M., Butt, J.N. and Cheesman, M.R., Electrochemical titrations and reaction time courses monitored in situ by magnetic circular dichroism spectroscopy. (2011) Anal. Biochem. 419: 110-116
v) Prisner, T., Rohrer M. and MacMillan F. Pulsed EPR spectroscopy: biological applications (2001) Annu Rev Phys Chem. 52: 279-313.

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