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Characterising and Developing New Enzymatic Pathways to Novel Antibiotics and Anticancer Agents – PhD CASE Studentship in collaboration with Unilever


Department of Chemistry

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Prof J Micklefield , Prof P Cai , Dr A Day No more applications being accepted Funded PhD Project (UK Students Only)
Manchester United Kingdom Biochemistry Biotechnology Genetics Microbiology Molecular Biology Organic Chemistry Pharmaceutical Chemistry Structural Biology Synthetic Chemistry

About the Project

New antibiotics are urgently required to treat infectious diseases, prevent the spread of microbial pathogens and to combat antimicrobial resistance (AMR). Most antimicrobial agents in use today are derived from natural products (secondary metabolites). In addition to antibiotics, natural products have also inspired the development of many anticancer, antiviral, immunosuppressive and cholesterol lowering agents. Most therapeutically important bioactive natural products are obtained from microorganisms in the environment. Plants are also prolific producers of bioactive compounds. However, plants often produce very low levels of natural products. Moreover, plants can be difficult to cultivate and manipulate making the optimisation and isolation of valuable plant natural products extremely difficult. In this project we aim to characterise the biosynthetic pathway to a family of plant natural products (alkaloids) which possess very promising antimicrobial and anticancer activity. Initially we will sequence the genome (DNA) and transcriptome (mRNA) of the plants that make the alkaloids to identify the genes encoding the enzymes required for the biosynthesis of thalkaloids. We will express these genes in E. coli or yeast cells, purify the enzymes and then characterise the reactions catalysed by each enzyme. Having characterised the enzyme, we will then transfer the entire pathway of enzymes into a microbial host strain (E. coli or yeast) to optimise production of the required alkaloid compounds. We will also obtain X-ray structures of key enzymes which can guide mutagenesis, changing the selectivity of enzymes on the pathway to generate novel alkaloids with improved antimicrobial or anticancer activity.

Training will be provided in biological chemistry, biochemistry, enzymology, structural biology (X-ray crystallography) and synthetic biology under the supervision of Professors Jason Micklefield, Patrick Cai and Anil Day. Candidates are not expected to have expertise across the Chemistry-Biology disciplines at the outset; above all, scientific curiosity and a desire to work in a multidisciplinary environment are most important. The project will be carried out in the Synthetic Biology Centre (http://synbiochem.co.uk) at the Manchester Institute of Biotechnology  (http://www.mib.manchester.ac.uk) and will also involve close interactions with scientists from Unilever who have interests in plant derived natural products for health/personal care products. This PhD CASE studentship will include a placement period at Unilever where the student can obtain additional training and skills in world leading industrial biotechnology labs. Students from Chemistry or Biological Sciences degree programmes, who possess a desire to do cutting edge research at the Chemistry-Biology interface are encouraged to apply.

Academic background of candidates

Applicants are expected to hold, or about to obtain, a minimum upper second class undergraduate degree (or equivalent) in Chemistry, Biological Sciences or a related discipline. A desire to do cutting edge research at the Chemistry-Biology is desirable. Training will be provided in biological chemistry, biochemistry, enzymology, structural and synthetic biology Candidates are not expected to have expertise in these areas at the outset; above all, scientific curiosity and a desire to work in a multidisciplinary environment are most important.

Contact for further Information

Enquiries including a brief cover letter & CV should be sent to:  [Email Address Removed]; include the project title in the email heading.

[Email Address Removed]

http://www.micklefieldlab.chemistry.manchester.ac.uk

https://www.research.manchester.ac.uk/portal/jason.micklefield.html

https://twitter.com/Micklefield_Lab

Professor Patrick Cai

https://www.cailab.org

Dr Anil Day

https://www.research.manchester.ac.uk/portal/anil.day.html


Funding Notes

This is a 4 year PhD CASE studentship funded by Unilever. The funding will cover fees and stipend.
We expect the programme to commence in September 2021.

References

[1] A vitamin K-dependent carboxylase is involved in antibiotic biosynthesis. B. J. C. Law, Y. Zhuo, D. Francis, M. Winn, Y. Zhang, M. Samborskyy, A. Murphy, P. F. Leadlay & J. Micklefield. Nature Catalysis 2018, 1, 977-984 (https://doi.org/10.1038/s41929-018-0178-2).
[2] Integrated Catalysis Opens New Arylation Pathways via Regiodivergent Enzymatic C-H Activation. J. Latham, H. H. Sharif, J.-M. Henry, B. R. K. Menon, S. A. Shepherd, M. F. Greaney, J.Micklefield. Nature Commun. 2016, 7, 11873 (http://dx.doi.org/10.1038/NCOMMS11873)
[3] Engineering orthogonal methyltransferases to create alternative bioalkylation pathways. A. J. Herbert, S. A. Shepherd, V. A. Cronin, M. R. Bennett, R. Sung & J Micklefield* Angew. Chem. Int. Ed. 2020, 59, 2–9. (https://doi.org/10.1002/anie.202004963).
Also see N&V Nature Chemistry 2020, 12, 791–792 (https://doi.org/10.1038/s41557-020-0533-1)
[4] Structure and Biocatalytic Scope of Coclaurine N-Methyltransferase. M. R. Bennett, M. L. Thompson, S. A. Shepherd, M. S. Dunstan, A. J. Herbert, D. R. M. Smith, V. A. Cronin, B. R. K. Menon, C. Levy, J. Micklefield Angew. Chem. Int. Ed. 2018, 57, 10600-10604 (https://doi.org/10.1002/anie.201805060).
[5] Rapid pathway prototyping and engineering using in vitro and in vivo synthetic genome SCRaMbLE-in methods. Cai et al. Nature Commun. 2018, 9, 1936. (https://doi.org/10.1038/s41467-018-04254-0)
[6] Design of a synthetic yeast genome. Cai et al. Science 2017, 355, 1040-1044. (https://doi.org/10.1126/science.aaf4557


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