Discovery, Evolution and Application of Enzymes

We are interested in the chemistry at the interface with biology. For example, we developed diverse chemical, biochemical and physico-chemical tools for the synthesis and analysis of complex small and large bioactive molecules, in particular glycolipids, polysaccharides, and glycoproteins. We are particularly interested in biocatalysis, the development of enzymes as catalysts for applications in organic synthesis [Nature Primer 2021,1,46 / Nature Catalysis 2021, 4, 98]. Over the years we have developed a range of biocatalysts that can mediate organic reactions with unprecedented chemo-, regio- and stereoselectivity, including alcohol oxidations, C-H oxidations using novel self-sufficient P450 monooxygenases, C-C bond formations and conjugation reactions to generate peptides and complex glycosides. Very recently we have taken this field forward by combining these individual biocatalysts to generate novel ‘synthetic’ biochemical pathways in ‘one pot’ both in vitro [JACS 2012,134,4521] and in single whole-cell systems. This work has led to new de novo biosynthetic pathways, such as catalysis of a formal stereoselective C-H amination of simple organic compounds [ACIE 2016,55,1511] and synthesis of chiral heterocycles [ACS Catalysis, 2017, 7, 2920] in the emerging area of de novo biosynthesis [ACS Catalysis, 2017, 7, 710].

Development of Glycoanalytics platform

Carbohydrates (such as sugars, glycans and polysachharides) provide the largest biomass on Earth and are central to many aspects of biotechnology. As such glycoscience and glycobiotechnology have broad applications in the development of biofuels, biomaterials and food stuffs from recycled and readily available biomass, as well as in medical research. Through investigation of the chemistry, structure and interactions associated with various carbohydrate molecules, it is possible to understand mechanisms of disease, develop novel glyco-based therapeutics and replicate the natural biosynthesis of glycans for synthetic purposes. However, the complex and diverse molecular nature of carbohydrates means that there is an urgent need to develop robust, wide-ranging synthetic and analytical methodologies for general use in this area.

The glycan array work initiated close and fruitful collaborations in mass spectrometry of carbohydrates with the Michael-Barber Centre at MIB in Manchester (in close collaboration with Gaskell, Eyers and Barran, Compagnon at Lyon). This work has resulted in the first report of a fragment-based carbohydrate sequencing approach [Nature Chem 2014,6,65; Analytical Chemistry 2017, 89, 4444 & 4540; Schindler et al. Nature Commun 2017,8,973], which uses hyphenated mass and ion mobility spectrometry techniques to provide stereochemical assignment of both sugar building blocks and glycosidic linkages in carbohydrate polymers. This stereochemical assignment of carbohydrate fragments in the gas phase fills the final gap in the fundamental toolkit required for fast, high-resolution and sequence-independent structure elucidation and is a step-change in the sequencing of carbohydrates.