Discovery, development and application of novel amine and imine biocatalysts for the synthesis of natural products, their analogues and other privileg

Natural products, their analogues and other privileged structural motifs are of exceptional importance to many members of the scientific community, particularly those in the pharmaceutical and agrochemical industrial sectors. A large percentage of these high value entities incorporate nitrogen-containing substructures within their frameworks. With respect to natural products, two important enzyme classes, which are involved in their biogenesis, are the monoamine oxidases and imine reductases. The former of these catalyse the oxidation of substrate amines to generate high energy, imine intermediates whereas the latter catalyse the reduction of imines to form enantiomerically pure chiral amines. Previous collaborative research by the Turner and Whitehead groups has demonstrated application of the two enzyme classes, both individually and in tandem, for the preparation of industrially relevant structures such as chiral 3-substituted piperidines and functionalised benzylic amines. Preparative scale synthetic work has resulted in the successful preparation of analogues of the anti-diabetes drug Preclamol, a biologically potent analogue of the anti-tumour drug WP1066, and a key intermediate in the synthesis of the anti-cancer agent Niraparib.
The goal of this cross-disciplinary project is to (i) develop and expand the available "toolbox" of engineered monoamine oxidases and imine reductases and (ii) develop efficient preparative synthetic approaches for the preparation of specific substrates for these biocatalysts - this will ultimately lead to novel chemo-enzymatic routes to privileged structural building blocks as well as bio-active natural and unnatural products.
This is a multi-disciplinary project which will provide a PhD student with 'state-of-the-art' training in the combined fields of advanced organic synthesis, biocatalyst development and advanced mass spectrometry. In a broader context, a successful outcome to the project will have widespread impact on two fronts:
- it will demonstrate the extensive and, so far, mostly untapped potential of amine and imine/iminium ion biocatalysts as versatile catalysts for efficient preparative scale chemical reactions;
- it will provide researchers in the synthetic, medicinal and biological chemistry fields with efficient routes to privileged structural motifs, versatile synthetic building blocks and natural product-like scaffolds which would otherwise be difficult, or impossible, to obtain.
These impacts clearly demonstrate that the project sits firmly within the BBSRC theme of Industrial Biotechnology. Furthermore, the synergistic scientific expertise of the three members of the supervisory team is expected to result in the development of novel and effective approaches to the discovery, optimisation and application of new biocatalysts which are of great importance to both industrial and academic research communities.