Non-Enzymatic Catalysis in the Microbial Cell Interior

Reducing our society's reliance on non-renewable fossil fuels is arguably one of the most important challenges facing the modern chemical industry.

Traditionally, the fields of synthetic organic chemistry and metabolic engineering have represented two independent solutions to this challenge. Whereas synthetic organic chemists use largely non-biological reagents to manipulate small molecules in multi-step processes, metabolic engineers encode synthetic pathways within a sequence of DNA and overproduce target compounds via fermentation. However, despite the respective (and potentially complementary) benefits of these two approaches, metabolic engineering and synthetic organic chemistry have existed as largely separate disciplines for over a century.

This Fellowship will merge these two fields by developing non-biological reactions for use within metabolically engineered microbial cells. It will, uniquely, focus on exploring these reactions in the cell interior and within designer metabolic pathways. Reactions will be targeted to various compartments of the cell using a "click" reaction between the catalyst scaffold and a genetically-encoded unnatural amino acid. Ultimately, this will enable microbial cells to synthesise molecules that are not found in Nature and therefore cannot be genetically encoded.

In doing so, this will also answer fundamental questions in the field, namely:

(i) Can non-enzymatic catalysis be truly integrated within an engineered metabolic pathway?
(ii) Can interactions between chemical catalysts and biomolecules within the cell enhance catalysis in vivo?
(iii) If so, can the chemical environment of the cell interior support modes of catalysis that are currently not possible in organic solvent?

Overall, this approach represents a unique solution to the problem of renewable chemical manufacture and will dramatically increase the range of small molecules that can be produced from biological feedstocks using engineered microbial cells.

This project will address the critical limitation of a purely synthetic biology approach to small molecules synthesis by enabling the simultaneous use of chemical and biological catalysts in living microbial cells. By integrating abiotic reactions into designer metabolic pathways, the MICRO-CAT project will dramatically increase the range of small molecules that can be accessed from renewable feedstocks via microbial fermentation. As such, the impact of this research will be far-reaching and widespread.

Economic Impact: By reducing the cost of medicines to patients, and by diminishing these drugs' reliance on the availability of fossil fuel resources, such treatments will be made available to more patients for longer. This creates immediate economic benefit to the UK via sustained employment and reduced healthcare needs, and will ultimately lead to economic impact in the longer term through increased public acceptance and sustained commercial activity. Continuing the UK's tradition as a leading investor in emerging science in this area will attract investment and employees on the international stage. This will be no more crucial than in the coming years, and will ensure the long-term global performance and overall economic competitiveness of the UK in the biotechnology era. Impact in this area will be realised through a series of lectures, communications with local devolved and national governments via learned societies and the establishment of a spin-out company focussed on the development of chemical methods to manipulate cellular bioprocesses.

Industrial Impact: The development of abiotic catalysts for use in metabolic pathway design will stimulate efforts to develop sustainable bio-processes to high-value chemicals and synthetic intermediates. This will be transformative across multiple industries that currently rely on energy- and resource-intensive multi-step organic synthesis - i.e. the fine chemical, pharmaceutical, agrochemical, fragrance, flavouring, cosmetics, polymer and industrial biotechnology sectors. The novelty of this approach will therefore provide underpinning knowledge in the chemical and biosciences with broad utility across academia and industry. The impact of this project will also extend to improving existing bioprocesses, in particular those where metabolites are extracted and further manipulated via chemical synthesis. This will provide a cost-saving benefit to both the company and the end-user. Industrial impact will be realised via interactions with IBioIC, SCI, Edinburgh Innovations and will be directly supported throughout the Fellowship by the School of Biological Science's Commercial Relations Manager and the Head of Chemical Biology at Ingenza.

Public and Social Impact: By establishing a novel approach to the bio-based manufacture of small molecules of broad industrial significance the MICRO-CAT project will have both short- and long-term impact in the public domain. In the short-term, pharmaceutical products could become less costly as a result of these bioprocesses. In the longer-term, this project will help diminish the environmental impact of the petrochemical industry by diminishing our reliance on non-renewable fossil fuels and championing the use of engineered cellular systems as viable replacements. This will impact the health of, and healthcare available to, future generations. This impact will be realised at a societal level through a concerted series of public engagement activities, focussed on providing evidence of how biotechnology can diminish the impact our society is having on our planet and how this can positively impact our everyday lives. This will also be realised through social and online media presences, podcasts and short TV productions, and public laboratory demonstrations. The educational impact of the MICRO-CAT project will be pronounced and realised through a series of research-led teaching endeavours at the University of Edinburgh and beyond.