Selective methylation and alkylation using methyl transferases

Professor Helen Hailes, Department of Chemistry, University College London
Professor John Ward, Department of Biochemical Engineering, University College London
Professor Tom Moody, Almac Sciences

project details

This iCASE BBSRC PhD studentship is a collaboration between Professor Helen Hailes’ and Prof John Ward’s groups at UCL and Almac Sciences

Methyl groups can have a significant beneficial effect on the physicochemical and biological properties of bioactive compounds [1]. However, it is very difficult to achieve selective methylation reactions using traditional synthetic approaches and typically, toxic reagents such as methyl iodide are used. Enzymatic methylation provides a very valuable alternative method using methyl transferases (MTs) which have received comparatively little attention to date in biocatalytic syntheses [2]. They are particularly useful enzymes for the regioselective methylation of compounds as well as the diversification of compound libraries. In recent work we have started to investigate the cloning and use of MTs as well as generating the expensive co-factor S-adenosyl methionine (SAM) in situ using methionine adenosyltransferases (MATs) [2-4]. In preliminary studies we have used MATs and MTs for the selective methylation of tetrahydroisoquinolines, together with 5’-methylthioadenosine/S-adenosyl homocysteine nucleosidase (MTAN).

In this interdisciplinary project we will develop MTs and cofactor supply systems in enzymatic reaction cascades with a range of compounds for the selective methylation of O-, N- and C-groups. In addition, we aim to integrate the in situ alkylation of enzymatically generated hydroxyl or amino groups formed via other enzymes to ensure the construction of highly integrated new reaction cascades towards heterocyclic compounds using SAM and SAM analogues.

The Hailes’ group in Chemistry and Ward group in Biochemical Engineering have track records in the development of new sustainable synthetic and biocatalytic strategies including the construction of enzyme cascades and enzyme discovery. Initially MTs will be used in biocatalytic methylations with heterocyclic substrates such as alkaloids [5], as well as alcohols and amines, to establish regio- and stereoselectivities. Other enzymes will also be incorporated to produce amines [6], alcohols or alkaloids [7] in situ with a view to establishing novel enzyme cascades. In addition, new O-, N-, C-MTs will be discovered using metagenomic and bioinformatics strategies and these will be screened to establish the substrate scope. If required MT mutagenesis will be carried out to enhance enzyme performance. As the project progresses, MTs with other-SAM analogues such as allyl-SAM, synthesised in situ from MAT and allyl-methionine, will be used to give 3- enzyme one pot allylation reactions. In the final year, building upon successful results, extension to other enzyme cascades and a reaction scale-up will be explored together with a placement (minimum 3 months) at Almac Sciences.

Overall, the aim of the PhD is to develop the use of methyl transferase enzymes in selective alkylation reactions and to construct novel enzyme cascades for the sustainable synthesis of structurally diverse compounds.

references

  • 1. H. Schonherr, et al., Angew. Chem. Int. Ed. 2013, 52, 12256.
  • 2. M. R. Bennett, et al., Curr. Op. Chem Biol., 2017, 37, 97.
  • 3. J. Siegrist, et al., FEBS Lett., 2017, 591, 312.
  • 4. S. Mordhorst, et al., Angew. Chem. Int. Ed., 2017, 56, 1.
  • 5. Y. Wang, et al., Angew. Chem. Int. Ed., 2019, 58, 101206.
  • 6. L. Leipold, et al., Green Chem., 2019, 21, 75.
  • 7. R. Roddan, et al., ACS Catal., 2019, 9. 9460.

eligibility and application

Applicants must hold, or be expected to achieve, a first or high upper second-class undergraduate honours degree or equivalent (for example BA, BSc, MSci) or a Masters degree in a relevant subject. This project is funded by a 4-year BBSRC studentship, applicants should ensure they have understood the funding eligibility criteria for these studentships. Unfortunately international students are not eligible for programme funding on this project.


Applicants should have, or expect to gain, at least a 2.1 honours or equivalent at Masters level in Chemistry, Chemical Biology or a related discipline. They should be self-motivated, be keen to work on a collaborative interdisciplinary project with industry and have excellent experimental skills. Good communication skills (both presentation and writing skills in English) are also essential.


For more information regarding the project, please contact Professor Helen Hailes


Your application and supporting documents should be sent in a single email to LIDo.Admissions@ucl.ac.uk When applying for iCASE projects the applicant should also include the iCASE Selection Form.


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