Bioprocess: Enzymatic Cascade Driven Asymmetric Reductive Carboxylation

About the Project

This BioProcess_IDLA PhD project will develop tools, knowledge and training in world-class biocatalysis by engineering two distinct cofactor dependent enzymes to yield asymmetric acid building blocks. The widespread UbiD family of prFMN-dependent reversible decarboxylases readily interconvert unsaturated hydrocarbons with the corresponding alpha,beta-unsaturated acid [1,2]. The Leys and Hay groups have been at the forefront of determining the mechanism and of the application of these enzymes. While the corresponding equilibrium is poised towards decarboxylation under ambient conditions, combining UbiD with other enzymes catalysing an irreversible reduction offers scope for CO2 fixation under ambient conditions, as previously demonstrated by coupling ferulic acid decarboxylase (Fdc) to carboxylic acid reductase (CAR) yielding an alpha,beta-unsaturated aldehyde [3].

We seek to expand the scope for UbiD mediated Csp2-H activation by combining Fdc with other enzymes to achieve reductive carboxylation yielding the corresponding saturated acid. The combination of Fdc and selected reductases has scope to afford asymmetric reductive carboxylation by virtue of the regioselective Fdc carboxylation and stereospecific reduction. Combined with biophysical studies (including advanced spectroscopy, computational modelling and structural biology), we will use laboratory evolution to generate variants with suitable properties in terms of substrate scope/activity. The groups of Leys, Green and Hay are co-located in the MIB and have access to relevant world-class infrastructure, Larrosa is housed in recently renovated Chemistry building.

The groups are well funded through a range of UKRI/industrial (collaborative) projects and frequently publish joint papers.

About the programme

Join experts in industry and academia working to sustainably manufacture the complex and diverse molecules needed by modern society.

Industrial manufacturing is at a turning point. Many conventional production routes rely on non-renewable resources, harmful chemicals, and energy-intensive steps. Biocatalysis using engineered enzymes offers a proven solution.

Led by The University of Manchester in collaboration with AstraZeneca, The Universities of Bristol and York alongside other leading industrial partners, BioProcess aims to train the next generation of scientists in the skills needed to realise full the potential of biocatalysis, protein engineering and biomanufacturing for the UK bioeconomy.

Training

BioProcess aims to train the next generation of bio-innovators. Our interdisciplinary programmes prepare PhD students and researchers with the real-world skills to apply biocatalysis, protein engineering and sustainable manufacturing in industry.

We offer:

• PhD projects co-developed with industry and aligned with real manufacturing challenges
• advanced theoretical and practical skills training provided by a mixture of industry and academic project partners covering structural biology; biophysical and analytical methods; computational modelling; directed evolution; process modelling and development; digital skills
• Access to a network of elite partners and mentors
• A strong track record of impact, including a free online course in industrial biotechnology with over 10,000 learners to date.

Strong foundations in Biocatalysis:

Formerly CoEBio3, our centre has a focus on delivering solutions with real impact in pharmaceutical and chemical manufacturing with our industry partners. Our work has already enabled major industrial advances

• Commercialised over 1,000 enzymes
• Covering 20+ reaction types, significantly expanding biocatalytic options for manufacturing.
• Pioneered metal-free processes
• Reducing reliance on costly and hazardous precious metal catalysts.
• Delivered high-performing biocatalysts
• Engineered industry-ready enzymes suitable for large scale pharmaceutical manufacturing.

We’ve also helped shape national policy. In 2018, our researchers co-authored the UK strategy report Growing the UK Industrial Biotechnology Base, supporting government plans for a £440 billion bio-economy by 2030.

Eligibility

Applicants should have, or expect to achieve, at least a 2.1 honours degree or a master’s (or international equivalent) in a relevant science or engineering related discipline.

How to apply

To be considered for this project you’ll need complete a formal application through our online application portal.

Applications should be submitted through the BioProcess IDLA Website (https://www.mib.manchester.ac.uk/research/centres/coebio3/), where you can find a step-by-step guide to the process. Further information about the IDLA is also available. Informal enquiries can be made by emailing sarah.shepherd@manchester.ac.uk.

Please see individual project deadlines. Applications received after the deadline will not be considered.

Funding Notes

Successful applicants will be awarded a 4-year studentship covering:

• Tuition fees paid at Home student rate*
• A tax-free stipend to help with living costs, set at the UKRI minimum rate
• A Research Training and Support Grant to cover travel expenses and project consumables associated with your research including conference attendance, secondments, and other research and training activities
• A flexible budget for personal development and training

Additional funding is available to support a range of IDLA activities, such as institutional visits, outreach and hands-on practical training.

*A limited number of IDLA studentships may be awarded to international students each year. We strongly encourage international applicants to discuss tuition fee waivers during the interview stage, so that potential fee reductions or additional scholarship support through the host university can be explored. Any waiving of international fees will be considered on a case-by-case basis by the host institution.

References

1. Leys (2018) Flavin metamorphosis: cofactor transformation through prenylation. Curr. Opin. Chem. Biol. 47, 117-125
2. Aleku et al. (2021) Synthetic Enzyme-catalysed CO2 fixation reactions. ChemSusChem 14, 1781-1804
3. Aleku, et al. (2020) Enzymatic C–H activation of aromatic compounds through CO2 fixation. Nat. Chem. Biol. 16, 1255–1260