James Marshall

Biocatalytic Asymmetric Reduction Amination Using Reductive Aminases (RedAms)

University of Manchester

Prof. Nicholas Turner

Prozomix

I am PhD student at the Manchester Institute of Biotechnology (MIB) in the University of Manchester under Professor Nicholas Turner. My primary research field is Biocatalysis and I will be researching into a class of NADP(H)-dependent enzymes termed Reductive Aminases (RedAm), a sub-class of the Imine Reductase (IRED) class of enzymes. These enzymes catalyse the coupling of carbonyl compounds to amines to synthesise chiral amines through the formation and reduction of an immonium ion intermediate. This reaction is of particular interest in the pharmaceutical and agrochemical industry, as approximately 40% active pharmaceutical ingredients (APIs) are made up of one or more chiral amine building blocks. Biocatalysis to carry out reductive amination is becoming the most desirable option as enzymes offer many advantages over traditional chemistry methods.

As well as being based at the University of Manchester, the initial research will be undertaken with IBioIC's industrial partner Prozomix in order to utilise their in-house metagenomic libraries to mine for novel RedAm sequences. To clone the vast number of novel putative RedAm genes from the metagenomics libraries, I will be using Prozomix's high through proprietary cloning technology- GRASP. Once these enzymes have been expressed, these Reductive Aminases will be then characterised at the MIB with a defined panel of highly active amines and ketones to determine their enantioselectivity and their conversion rates.

Further characterisation of these enzymes will come from structural studies carried out in partnership with the University of York. X-Ray Crystallography will be used to determine domain and loop movements, as well as hopefully the catalytic mechanism. Mutagenesis with aid of structural studies will be used to broaden substrate scope on the most active novel RedAms. An additional aim is to carry out process optimisations on preparative scale reactions through potentially immobilizing RedAms and incorporating RedAms into cascade reactions. The overall objective of the PhD is to generate a generic biocatalytic platform for the catalytic enantioselective reductive amination.

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