Award details

Use of transaminase enzymes for the synthesis of pharmaceutical intermediates

Reference	BB/H016589/1
Principal Investigator / Supervisor	Professor Helen Hailes
Co-Investigators / Co-Supervisors	Dr Ian Taylor, Professor John Ward
Institution	University College London
Department	Chemistry
Funding type	Skills
Value (£)	83,281
Status	Completed
Type	Training Grants
Start date	01/10/2010
End date	30/11/2014
Duration	50 months

Abstract

unavailable

Summary

The use of enzymes and synthetic biology strategies hold significant potential for the synthesis of pharmaceutical intermediates, and sustainable syntheses of chiral amines are highly sought after since 70% of all pharmaceutical are derivatives of chiral amines. To date chiral amines have been generated using biocatalytic strategies predominantly via the kinetic resolution of racemic mixtures with hydrolytic enzymes, where only a 50% maximum yield can be achieved. A deracemization biocatalytic strategy has also been described [1,2], however, recently interest has focused of the use of transaminases (TAm) to generate chiral amines in a genuinely asymmetric transformation [3]. This has the potential for a process to be developed using transaminases that would yield 100% of the asymmetric product, resulting in less waste and a lower cost strategy to these important synthons. TAms catalyse the transfer of an amino group from a donor such as an amino acid, to an acceptor ketone or aldehyde moiety. While the alpha-TAms have a strong preference for an alpha-keto acid as the acceptor and the preferred donor is usually one of the 20 alpha-amino acids, the omega-transaminases can transfer an amino group to an aldehyde or a ketone and do not frequently have a requirement for the alpha-keto acid moiety [4]. They also have a broader range of amino donors that they can use. In previous work by Shin and co-workers [5] an omega-TAm used for the amination of a wide range of ketones and aldehydes, including aromatic substrates, was isolated from Vibrio fluvialis and we used the protein sequence of V. fluvialis JS17 omega-TAm to screen the genome databases for related enzymes [6]. This bioinformatics approach yielded several omega-TAms including one from Chromobacterium violaceum DSM30191 that can convert of a range of ketones and aldehydes, including aliphatic and aromatic 1,3-dihydroxy ketones, resulting in very high stereoselectivities in the product ((S)-amine) [6]. In a current, 12 month EPSRC Follow-on-Fund award (EP/G005834/1), this bioinformatics strategy to identify new TAms is being pursued to find further TAms that readily convert a range of aliphatic, cyclic and aromatic ketones and aldehydes. Our aim with a BBSRC industrial CASE project is to extend the bioinformatics screen to new groups of TAms and then use several of the TAms from the EPSRC project, and new TAms (including for example sugar-specific TAms and the omega, beta and gamma-TAms) which will be cloned and characterised as part of the project, for the synthesis of chiral amines of interest to the collaborating company Chirotech Technology Limited. This will enable application of the TAm biotransformation strategy in an industrial environment and establish key advantages and problems of translating this approach at a larger scale. References: [1] Turner, N.J. Curr. Opin. Biotechnol., 2003, 14, 401. [2] Pàmies, O.; Bäckvall, J.E. Trends Biotechnol., 2004, 22, 130. [3] Koszelewski, D.; Clay, D.; Rozzell, D.; Kroutil, W. Eur. J. Org. Chem., 2009, 2289. [4] Hwang, B.Y.; Byung-Kwan, C. B. K.; Yun, H.; Kinera, K. K.; Kim, J. Mol. Catal. B: Enz., 2005, 37, 47. [5] Shin, J.S.; Kim, B.G. Biosci. Biotechnol. Biochem., 2001, 65, 1782 [6] Kaulmann, U.; Smithies, K.; Smith, M.E.B.; Hailes, H.C.; Ward, J.M.; Enzyme Microb. Technol., 2007, 41, 628.

Committee	Not funded via Committee
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	Training Grant - Industrial Case

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