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Directed Evolution of Amine Dehydrogenases (AmDHs) for the Synthesis of Pharmaceutically Important Amines


   Department of Chemistry

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  Prof G J Grogan, Dr W Unsworth  No more applications being accepted  Competition Funded PhD Project (UK Students Only)

About the Project

Background: The asymmetric synthesis of chiral amines is one of the most significant reactions in the pharmaceutical sector as this functional group features in >40% of small molecule drugs. In addition to abiotic methods of chiral amine synthesis, enzyme-catalyzed reactions have also been the focus of interest as, in addition to selectivity, they offer more sustainable routes to amines without recourse to precious metal catalysts and hydrogen. In recent years we have described the discovery of NAD(P)H-dependent oxidoreductase enzymes that catalyze the asymmetric reductive amination of prochiral ketones to form amine products with high optical purity (Grogan, Turner (2017) Nature Chem., 9, 961-969) and which are now applied on multi-ton scale in industrial processes for the synthesis of chiral secondary amines (Kumar, Pfizer (2021) Nature Catal. 4, 775-782). In addition to these ‘Reductive Aminases’ (RedAms), we have also reported the discovery of natural ‘Amine Dehydrogenases’ (AmDHs) that catalyze the asymmetric reductive amination of ketones using ammonia (Grogan, Vergne (2019) Nature Catal., 2, 324-333) Ammonia is an amine donor that is not well recognised by RedAms; this is significant because AmDHs will enable complementary chiral primary amines to be prepared. In collaboration with Genoscope (a not-for-profit gene discovery institute in Evry, France), we have cloned, expressed and structurally characterised several natural AmDHs, and determined that they have great potential as biocatalysts for the synthesis of primary amines. We have also identified many interesting primary amine products as pharmaceutical precursors, which we propose may be accessible using AmDH catalysis, if the enzymes could be evolved for alternative specificity. This would represent the first attempt to apply directed evolution methods to the alteration or improvement of AmDH activity for process applications.

Objectives: To apply directed evolution to AmDHs for the creation of process-suitable biocatalysts for chiral primary amine synthesis.

Experimental Approach: [1] Synthesise ketone precursors and product standards for pharmaceutical amine targets (WPU lab); [2] Screen natural AmDH library for activity towards model ketones (GJG lab); [3] Apply random mutagenesis methods to selected AmDHs and use high-throughput (HT) screening to select mutants (GJG lab); [4] Structural characterisation of evolved AmDHs and rational mutagenesis for further improvement (GJG lab); [5] Application of evolved AmDHs to preparative scale aminations and characterisation of products (WPU lab).

Novelty: Following the discovery of natural AmDHs, there have been no examples of their engineering using directed evolution for improved characteristics. The potential is great, as evolved catalysts would present a superior alternative to industrial transaminase catalysts for primary chiral amine synthesis.

Training: The student will be supervised in the WPU lab and in the GJG group in the YSBL and will be trained in synthetic organic and relevant analytical chemistry, gene cloning, construct engineering, heterologous expression, biotransformations, gene mutation and relevant aspects of structural enzymology using X-ray crystallography. The project will also provide training in assays using HPLC, GC and GCMS and plate-based UV spectrophotometry for HT screening. The student will also benefit from compulsory programmes of postgraduate study and skills training offered through the Department of Chemistry, and frequent written and oral presentations. Regular contact with collaborators Genoscope through Zoom meetings will be maintained. Genoscope has generously offered to host the student at some point during the PhD and York will also host a Genoscope PhD student for a return visit. These interactions will ensure access to additional training, expertise and guidance throughout the project. All Chemistry research students have access to our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills: https://www.york.ac.uk/chemistry/postgraduate/cdts/

The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel: https://www.york.ac.uk/chemistry/ed/.

For more information about the project, click on the supervisor's name above to email the supervisor. For more information about the application process or funding, please click on email institution

This PhD will formally start on 1 October 2022. Induction activities may start a few days earlier.

To apply for this project, submit an online PhD in Chemistry application:

https://www.york.ac.uk/study/postgraduate/courses/apply?course=DRPCHESCHE3

You should hold or expect to achieve the equivalent of at least a UK upper second class degree in Chemistry or a related subject.  


Funding Notes

Fully funded for 3 years by the Department of Chemistry and covers: (i) a tax-free annual stipend at the standard Research Council rate (£15,609 for 2021-22), (ii) tuition fees at the Home rate, (iii) funding for consumables. See guidance for further details: https://www.york.ac.uk/chemistry/postgraduate/research/dept-stud/
Studentships are available to any student who is eligible to pay tuition fees at the home rate: https://www.york.ac.uk/study/postgraduate-research/fees/status/
Not all projects will be funded; candidates will be appointed via a competitive process.

References

Candidate selection process:
• You should hold or expect to receive at least an upper second class degree in chemistry or a chemical sciences related subject
• Applicants should submit a PhD application to the University of York by 28 February 2022
• Supervisors may contact candidates either by email, telephone or web-chat
• Supervisors can nominate up to 2 candidates to be interviewed for the project
• The interview panel will shortlist candidates for interview from all those nominated
• Shortlisted candidates will be invited to a panel interview on 30th or 31st March or 1stApril
• The awarding committee will award studentships following the panel interviews
• Candidates will be notified of the outcome of the panel’s decision by email

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