PhD Studentship - Re-tasking of Carboxylic Acid Reductase (CAR) to New Chemistries

The University of Manchester - MIB and School of Chemistry

Primary Supervisor: Professor Sabine Flitsch

Email: Sabine.flitsch@manchester.ac.uk

% of supervisory split (0-100%): 100%

Funding Source: CoEBio3

Expected student start date: September 2018

Duration: 3.5 years

Eligibility: Restricted to UK/EU applicants

Project description (this will be used as the basis for the project advert; maximum of 300 words)

The objective of this studentship is to develop new biocatalysts for the synthesis of fine chemicals and applications in medicinal chemistry. Carboxylic acids are common reagents in organic synthesis, and their interconversion to other functional groups generally requires activation to reactive acyl intermediates as the key step. In Nature, there are many enzymes that catalyse such activation, and a particularly interesting class are the carboxylic acid reductases (CARs). The structure of a CAR has recently been solved at Manchester and was shown to be modular with each step catalyzed by its dedicated subunit with intermediates passed on from subunit to subunit through the reaction cycle. This modular structure led us to explore the promiscuity of CARs towards new chemistries of carboxylic acids, in particular the introduction of amine nucleophiles that would react with the activated acyl-intermediates to generate amides.

The studentship is funded by CoEBio3 (www.coebio3.manchester.ac.uk) and provides a unique environment of academic and industrial open partnerships. The student will gain experience in a truly transdisciplinary environment and be trained in a number of generic techniques including biological chemistry, enzymology, molecular biology, protein chemistry and a number of analytical techniques, including nmr spectroscopy, mass spectrometry and liquid chromatography. The Flitsch group is housed in the Manchester Institute of Biotechnology (MIB) consisting of ca 5 postdoctoral researchers and 8 PhD students, all working on aspects of biocatalysis. Access to state-of-the art instrumentation in chemical biology will be provided. The University of Manchester supports further professional development of graduate students with training courses provided and encourages dissemination through talks at seminars, attendance at conferences and publications.

Related references (optional, maximum of 5 references can be added to advert)

[1] Gahloth, D. et al ‘Structures of carboxylic acid reductase reveal domain dynamics underlying catalysis’. Nature Chemical Biology, 2017, 13, 975-981. DOI:10.1038/NCHEMBIO.2434

[2] Wood, A. J. L. et al ‘Adenylation Activity of Carboxylic Acid Reductases Enables the Synthesis of Amides’. Angew. Chemie. Int. Ed, 2017. 2017, 56, 14498-14501. DOI: 10.1002/anie.201707918

[3] Yan, C. et al. ‘Real-time screening of biocatalysts in live bacterial colonies.’ J. Am. Chem. Soc., 2017, 139(4), 1408-1411. DOI: 10.1021/jacs.6b12165

[4] Yan, C. et al.  ‘Rapid and sensitive monitoring of biocatalytic reactions using ion mobility mass spectrometry’. ANALYST, 2016, 141(8), 2351-2355. DOI:10.1039/C6AN00617E. 

Contact for further Information

Flitschlab.com

Applicants are expected to hold, or about to obtain, a minimum upper second class undergraduate degree (or equivalent) in chemistry, biochemistry or related sciences. A Masters degree in a relevant subject or experience in enzymology is desirable. 

www.chemistry.manchester.ac.uk/study/postgraduate/researchdegrees/howtoapply

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Type / Role:

PhD

Location(s):

Northern England