Supervisors: Amanda Jarvis, Dominic Campopiano

Project Description:

Asymmetric catalysis is key to allow the synthesis of a whole range of products including bioactive molecules such as pharmaceuticals and agrochemicals. Enzymes are amazing asymmetric catalysts, providing high selectivities and activities under benign conditions. Recent work, has shown that natural metalloenzymes can be repurposed to perform unnatural reactions such as C-H amination,1 and organoborane synthesis.2

The Campopiano group has previously worked on a ferric binding protein (FBP) and shown that a number of other metals (e.g. Ti3) can be bound within the ferric binding site. The natural enzyme does not have any catalytic activity. The metal-binding site in rich with O (tyrosine) ligands, thus making it a potential alternative to chiral ligands, such as BINOL, for asymmetric Lewis acid catalysis. In this project, you will bring FBP to life as a Lewis acid catalyst for asymmetric reactions such as the Diels-Alder reaction and Mannich reaction. Protein engineering techniques, e.g. directed evolution, will be used to increase the activities and selectivities of the enzymes. This will result in introducing new chemistry into a previously inactive protein, providing new catalysts for the biological toolbox.  These enzymes will then be exploited using synthetic biology to develop biosystems for chemical synthesis.

Training:
Training will be provided in molecular biology (i.e. the growth, expression and purification of ferric binding proteins, and subsequent genetic optimisation via either site-directed or random mutagenesis), structural biology and bioinorganic chemistry (understanding metal binding of the proteins), and in the organic chemistry needed for catalytic testing.

References:

1. Dydio, P.; Key, H. M.; Hayashi, H.; Clark, D. S.; Hartwig, J. F. J. Am. Chem. Soc. 2017, 139, 1750.
2. Kan, S. B. J.; Huang, X.; Gumulya, Y.; Chen, K.; Arnold, F. H. Nature, 2017, 552, 132-136.
3. Guo, M.; Harvey, I.; Campopiano, D. J; Sadler, P. J., Angew. Chem. Int. Ed., 2006, 45, 2644-2654,

To apply for this project, please go to this link.