Community Research and Development Information Service - CORDIS

ERC

GCGXC Report Summary

Project ID: 614779
Funded under: FP7-IDEAS-ERC
Country: United Kingdom

Periodic Report Summary 2 - GCGXC (GenoChemetics: Gene eXpression enabling selective Chemical functionalisation of natural products)

GenoChemetics blends together synthetic biology and synthetic chemistry to enable expeditious access to new to nature bioactive natural products. Natural products are critical to human medicine (60% of medicines are based on natural products), analogues are needed to explore modes of action and improve bioactivities and bioavailiabilities, but such analogues can be very hard to access using chemical synthesis alone. GenoChemetics takes organisms capable of producing bioactive compounds of interest and introduces genes that encode the introduction of a chemically orthogonal and reactive handle into the natural product- thus gene insertion enables selective chemical diversification.
This powerful approach requires the assembly of multidisciplinary team and we are indebted to the ERC for enabling this.

The first period of our research has been successful – tryptophan is a key residue in many bioactive natural products, and is also crucial to protein folding and fluorescence. There is great potential for modulating compound and protein properties through selectively derivitising tryptophan. Until our work in 2008, no one had explored the challenging cross-coupling derivitisation of tryptophan, and our work in this area has been enabling.
Funded by the ERC, we have now found strikingly different halogenases, we have introduced halogenases to make new to nature halonatural products, and we have recently developed mild conditions for the ketoarylation and the Sonogashira diversification of halotryptophans and new to nature halometabolites.
Our ambition was to develop GenoChemetics approaches that could be utilized in living cells. We have achieved this, using synthetic biology approaches to construct pathways in robust microbial hosts, introducing halogenase genes, and developing very mild aqueous and aerobic conditions for our cross coupling reaction. Crucial to our success for living GenoChemetics was the careful development of culture media that could sustain living cells without competing with the reaction.

Such an approach is exciting, not only does it draw metabolic flux through a pathway but also has the potential to enable directed evolution experiments in the presence of living cells and opens the possibility of enable the detection and tracking of metabolites in organisms. We are exploring series of potential applications collaboratively. This work has led to ~ 40 invitations to deliver seminars internationally.

Reported by

THE UNIVERSITY COURT OF THE UNIVERSITY OF ST ANDREWS
United Kingdom
Follow us on: RSS Facebook Twitter YouTube Managed by the EU Publications Office Top