This module concerns the engineering of biosynthetic pathways for synthesis of organic chemicals for use as pharmaceuticals, agrochemicals, flavours/fragrances and fuels. Biosynthesis enables sustainable manufacture of complex molecules in multistep routes using fermentation from renewable feedstocks under benign conditions. The combination of synthetic chemistry with biosynthesis provides an efficient avenue to novel compounds for screening as drugs. The strategies and challenges for production of organic chemicals through biosynthetic pathways will be described and illustrated with examples drawn from the biosynthesis of different classes of secondary metabolite.

• Propose intermediates and reaction pathways for the biosynthesis of a given metabolite.  

• Choose strategies to engineer enzymes and metabolic pathways to produce a compound of a given structure. 

• Retrieve, interpret and communicate data, findings and procedures relating to biosynthesis from journals and databases. 

The module will be delivered primarily using lectures (22 h across one semester) where the principles of biosynthesis of different classes of secondary metabolite will be introduced including case studies of engineering from the literature. In addition, lectures will include worked problems and informal ad hoc formative activities.  

Workshops (two formative, one summative) will be used to enhance and assess problem-solving and literature searching skills. 

Students will practice applying the concepts of synthetic organic chemistry to enzyme catalysed biosynthetic pathways. Students will develop skills in proposing appropriate starting materials and enzymes to synthesise a given target structure. 

  Chemistry specific skills will include: 

• Assignment of metabolites to a particular pathway, and proposal of biosynthetic intermediates and transformations;   

• Apply strategies for modifying a biosynthetic pathway to increase yields or produce novel products;  

• Predicting the outcome of biosynthetic processing of an unnatural substrate;   

• Choosing appropriate synthetic substrates for biosynthetic pathways to generate novel compounds.   

  Transferable skills:  

• Searching databases to find relevant chemical literature; 

• Synthesising and summarising information from multiple sources; 

• Proposing solutions to problems based on incomplete information;  

• Presenting chemical arguments in written form. 

Formative assessment: The first two workshops will be assessed formatively, and feedback provided either orally or in written form. This will give students an opportunity to revise the factual module content and to practice applying it to deduce and propose biosynthetic pathways. 

Summative assessment: A summatively assessed workshop in the form of an open-book exercise will test the ability to explain biosynthetic pathways, find information, propose pathways for production of previously unseen compounds, propose and interpret experiments in biosynthesis. 

  THE OPPORTUNITY FOR REASSESSMENT IN THIS MODULE: 

The reassessment will take place during resit examination period. The reassessment will take the same form as the original assessment. 

Rationale for engineering pathways in primary and secondary metabolism for sustainable production of complex organic chemicals. 

Biosynthetic pathways for common classes of secondary metabolite, with examples drawn from polyketides, terpenoids, alkaloids and non-ribosomal peptides. 

Strategies for modifying enzyme selectivity and activity – rational design, screening, directed evolution approaches.  

Case studies of engineering metabolite biosynthesis. 

Reconstituting metabolic pathways in new hosts (choice of host - considerations such as precursor availability, toxicity of intermediates, compartmentalisation, PTMs of pathway enzymes, accessory proteins).  

Efficiently creating molecular diversity by combining synthetic chemistry with biosynthesis (mutasynthesis) and combinatorial biosynthesis.