Novel Chemoenzymatic Approaches to 'Unnatural' Terpenes

Natural products constitute a rich source of molecules and materials, from which groundbreaking therapeutic agents for the treatment of human, animal and plant diseases derive, as well as valuable compounds of commercial and industrial use. In particular, terpenes constitute the most abundant class of natural products, with more than 75,000 characterised so far - including compounds of industrial and pharmaceutical significance, such as the antimalarial artemisinin, the anti-cancer agent taxol and natural rubber.

Terpene carbon backbones are assembled in a 'modular' fashion through consecutive condensation of isoprenyl-based building blocks. Moreover, terpene synthase intermediates undergo extensive diversification, generating highly complex structures that are very challenging to prepare by synthetic chemistry methods. The difficulty of producing terpenes via total synthesis, as well as the fact that terpene synthase-derived drugs and biomaterials are still mostly produced biosynthetically or harvested, means that new approaches to novel valuable terpenoid generation should to be explored.

The aim of this PhD project is to investigate and establish novel chemoenzymatic approaches to 'unnatural' terpenes, which may be as valuable, if not superior, to existing natural terpene products. This will be accomplished via the preparation of chemical probes capable of 'capturing' terpene intermediates throughout product assembly to gather in-depth pathway and mechanistic understanding; the preparation of chemical 'synthons' that can be uptaken and processed by engineered microorganisms and terpene pathways to generate the 'unnatural' molecules; the isolation and characterisation of these novel chemical entities, including the evaluation of their biological activity. The outcomes of this work will constitute the basis for the development of novel biocatalytic routes to diversified natural products.