Abstract: Natural products often require further chemical modification to improve their biological activities or physicochemical properties for therapeutic and other applications. However, many of the most promising natural products, particularly polyketides and nonribosomal peptides, are highly complex molecules which offer limited opportunity for semi-synthesis, and are invariably inaccessible through total synthesis on the scale required for drug development. Consequently, alternative biosynthetic engineering approaches are required, which can enable the rapid structural diversification and optimisation of promising natural product scaffolds. This lecture will cover our recent progress in elucidating and engineering biosynthetic pathways to generate novel antibiotics and other bioactive target compounds. In addition, the lecture will also describe how enzymes from secondary metabolism can be exploited for synthetic applications to create new reaction pathways in vitro and in cells. For example, we have shown that flavin-dependent halogenase enzymes can be used to regioselectively halogenate a range of non-native aromatic compounds. Through structure-guided mutagenesis we were able to improve the activity and also switch the regioselectivity of halogenases. In addition, we demonstrated how halogenases can be combined with chemocatalysts to afford regioselective and regiodivergent arylation and alkenylation of aromatic scaffolds. These one-pot chemobiotransformations combine the power of enzymatic C-H activation with transition metal catalysed cross-coupling chemistry to effect reactions that are not possible using biocatalysts or chemocatalysts alone.

Biography: Jason Micklefield is Professor of Chemical Biology within the School of Chemistry and the Manchester Institute of Biotechnology at the University of Manchester. He graduated from the University of Cambridge in 1993 with a PhD in Organic Chemistry and then moved to the University of Washington, USA, as a NATO fellow investigating various biosynthetic pathways and enzyme mechanisms. In 1995 he began his independent research career as a Lecturer in Organic Chemistry at Birkbeck College, University of London before moving to Manchester in 1998. Jason has made diverse contributions at the chemistry-biology interface in the areas of biocatalysis, enzyme mechanisms, biosynthesis, biosynthetic pathway engineering and development of RNA based regulatory tools (riboswitches).