Enzymes with an Expanded Amino Acid Alphabet

Combining computational design and directed evolution is a powerful approach to create enzymes for non-biological reactions. However, the range of chemistries accessible is restricted by Nature's alphabet of canonical amino acids, which contain limited functionality and are not optimal for many biocatalytic transformations. Genetic code expansion (GCE) allows the site-selective installation of 'chemically programmed' non-canonical amino acids (ncAAs) into enzyme active sites, providing opportunities to access organocatalytic mechanisms not represented in Nature. A useful example are thioureas, which are a valuable class of small-molecule organocatalysts capable of activating carbonyl compounds through dual hydrogen-bonding interactions to promote a broad range of chemical transformations.
Previously in the group, pyrrolysyl-tRNA synthetase/PyltRNACUA pairs have successfully been engineered to encode several lysine-derived thioureas in response to reassigned amber stop codons (UAG). We are currently working on expanding the scope of encodable thioureas and have so far successfully incorporated one urea analogue. With these translation components in hand, we will be able to explore a range of chemical transformations within computationally designed active sites, eventually optimising these enzymes via directed evolution. This approach thus combines the efficiency and selectivity of protein catalysts, with the broad range of reactivities accessible with small molecule organocatalysts.

iCAT will work with industry partners to create an holistic approach to the training of students in biocatalysis, chemocatalysis, and their process integration. Traditional graduate training typically focuses on one aspect of catalysis and this approach can severely restrict innovation and impact. Advances in technology and fundamental reaction discovery are rendering this silo-approach obsolete, and a new training modality is needed to produce the next generation of chemists and engineers who can operate across a far broader chemical continuum. iCAT will meet this challenge with a state-of-the-art CDT, equipping the next generation of scientists and engineers with the skills needed to develop future catalytic processes and create the functional molecules of tomorrow.

The UK has one of the world's top-performing chemical industries, achieving outstanding levels of growth, exports, productivity and international investment. The UK's chemical industry is a significant provider of jobs and creator of wealth, with a turnover in excess of £50 billion and a contribution of over £15 Billion of value to the UK economy [2015 figures]. iCAT will deliver highly skilled people to lead this industry across its various sectors, achieving impact through the following actions:

1. Equip the next generation of science and engineering leaders with the interdisciplinary skills and knowledge needed to work across the bio and chemo catalytic remit and build the functional molecules we need to structure society.

2. Provide a highly skilled workforce and research base, skilled in the latest methodologies, strategies and techniques of catalysis and engineering that is crucial for the UK's Chemical Industry.

3. Build the critical mass necessary to support effective cohort-based training in a world-class research environment.

4. Develop and disseminate new catalytic technologies and processes that will be taken up by industrial and academic teams around the world.

5. Encourage Industry to promote research challenges within the CDT that are of core relevance to their business.

6. Provide cohesion in the integration of biocatalysis, engineering and chemocatalysis to create a more unified voice for strategic dialogue with industry, funders and policy makers, and more generally outreach and public engagement.

7. Draw-in and bring together Industrial partners to facilitate future Industrial collaborations.

8. Benefit Industrial scientists through interactions with the CDT (e.g. training and supervisory experience, exposure to cutting-edge synthesis and catalysis etc).

9. Link with other activities in the landscape: bringing unique expertise in catalysis to, for example, externally-funded University-led initiatives, EPRSC Grand Challenge Networks, and the National Catalysis Hub.