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Development of engineered carboxylic acid reductases (CARs) for efficient synthesis of amides from amines and carboxylic acids


Project Description

Background – AstraZeneca has provided a set of real world targets for demonstration of the benefits of biocatalysis in synthetic strategies. These targets present excellent opportunities for the development of biocatalysts for both reductive amination (Reductive Aminases – RedAms) and amide bond formation (carboxylic acid reductases – CARs) both of which have been recently discovered at the University of Manchester. Reductive aminases have been shown to catalyse reductive amination between primary/secondary amines and ketones/aldehydes.1 In a proof-of-concept study, engineered CARs have recently been shown for the first time to catalyse amide bond formation between carboxylic acids and amines.2 Retrosynthetic analysis of the AZ drug candidates reveals two pathways for synthesis utilising CARs and RedAms.

Aims – Synthesis of the AZ target compound requires engineered CARs which are able to couple carboxylic acids, either aliphatic or aromatic, with primary amines. We shall use our recently reported structures of CARs to aid in the redesign of these enzymes to accept a broader range of carboxylic acids and amines.3

Year 1 – Screening of our in house libraries of CARs to identify appropriate enzymatic activity.
Year 2 – Engineering of identified CARs for enhanced activity.
Year 3 – Development of gram scale biotransformations.
Year 4 – Development of enzymatic cascade coupling CARs with RedAms.

We welcome applications from graduates with a good UK honours undergraduate degree (1st class or a high 2i), or a first degree with an additional masters degree or international equivalent, in chemistry, biochemistry, biology or another aligned science subject. Applicants should be looking for a challenging, interdisciplinary research training environment.

All applicants should send their CV and covering letter to Dr Ian Rowles (CBNM Project Manager) . Applications will be reviewed as they are received until a candidate is selected; therefore candidates are encouraged to apply early.


Funding Notes

This is a 4 year studentship jointly funded by the EPSRC, AstraZenca and the University of Manchester, covering all fees and stipend (£14.777 in September 2018). Open to UK/EU applicants only.

The start date for this PhD prgramme will be September 2019.

References

1. G. Aleku et al., Nat. Chem., 2017, 48, 1080
2. A. Wood et al., Angew. Chem. Int. Ed., 2017, 56, 14498;
3. D. Gahloth et al., Nat. Chem. Biol, 2017, 13, 975
4. G.-D. Roiban et al., ChemCatChem., 2017, 9, 4475


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