Enabling Native Amine Dehydrogenases (AmDHs) for the Production of Chiral Amine Pharmaceuticals

Chiral Amines are found in a large proportion of currently administered small molecule drugs. The method of choice for their synthesis is the reductive amination of ketones, yet, while asymmetric methods of formation that employ transition metal catalysis exist, each is dependent on precious metals, such as iridium or rhodium, rendering such methods ultimately unsustainable. Enzymatic methods of reductive amination would therefore be attractive, as they would offer a sustainable alternative to amine formation with excellent stereoselectivity. Until recently, the only enzymes capable of enzymatic reductive amination were amino acid dehydrogenases (AADHs) that had been engineered to accept ketones, rather than keto-acids, as substrates [1,2]. However, more recent work by Genoscope in France has described the existence of native amine dehydrogenases (AmDHs) which will convert ketones into amines with the addition of ammonia [3]. However, each of these methods is currently limited to the production of primary amines.

As part of our continuing studies into enzymes that have potential for the industrial production of amines, we have recently described a ‘reductive aminase’ enzyme (RedAm) that will convert ketones into chiral amines with high stereoselectivity when supplemented with the biological reductant NADPH (Figure A) [4]. Significantly, the enzymes are able to catalyse the asymmetric reductive amination of ketones with primary amines to form secondary amine products, such as the anti-Parkinson’s drug (R)-rasagiline. We have determined the structure (Figure B) of this and other enzymes as a first step to the structure-guided engineering of the enzymes.

In collaboration with several partners, we are working towards the rational engineering of these catalysts for expanded substrate specificity and process suitability. In this project we will look to apply reductive aminases for the preparative-scale synthesis of chiral amines of interest, using novel structures as a basis for engineering mutants capable of using a wider range of amines. This will result in an expanded portfolio of enzymes for the direct asymmetric formation of secondary amine products.

The project will involve aspects of biological chemistry, organic chemistry and protein engineering, including X-ray crystallography. The successful applicant will have or expect to obtain, a degree in Chemistry and Biochemistry and should have taken relevant options in the later years of their degree.

[1] Abrahamson, Angew. Chem. Int. Ed. 2012, 51, 3969; [2] Abrahamson, Adv. Synth. Catal. 2013, 355,1780; [3] Mayol, Catal. Sci. Technol. 2016, 6: 7421. [4] Aleku, Nature. Chem. 2017, 9, 961.

All research students follow our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills. All research students take the core training package which provides both a grounding in the skills required for their research, and transferable skills to enhance employability opportunities following graduation. Core training is progressive and takes place at appropriate points throughout a student’s higher degree programme, with the majority of training taking place in Year 1. In conjunction with the Core training, students, in consultation with their supervisor(s), select training related to the area of their research. The iDTC themes are broad, interdisciplinary, and fit within the Department’s research expertise. Themes are flexible and adapt in line with the evolving research landscape. Each theme has a leader who oversees the training offered. Students may select courses from other themes where appropriate.

In addition to the transferable skills and current awareness options offered as part of the iDTC, Scientific Training will include aspects of organic chemistry and synthesis, analytical chemistry, molecular biology and protein engineering and X-ray crystallography in the York Structural Biology Laboratory.

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/. This PhD project is available to study full-time or part-time (50%).

This PhD will formally start on 1 October 2019. Induction activities will start on 30 September.