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GenoChemetics: Gene eXpression enabling selective Chemical functionalisation of natural products

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

GenoChemetics: Gene Installation Enabling Synthetic Diversification, represents a powerful approach of combining Synthetic Biology and Synthetic Chemistry to enable natural product diversification.

We opened a new field and led the way using enzymatic halogenation and cross-coupling enabling C-H activation. Our published the first example of this in 2010.
The ERC grant has enabled us to significantly extend and develop these methodologies, and we have demonstrated the first example in vivo.

Individual tools that have been developed throughout the project are also noteworthy in their own right.
A toolbox of aqueous compatible cross-coupling reactions that may be used on natural products and biomolecules and are compatible with sensitive motifs, have been developed including:
-Sonogashira, Heck, Buchwald Hartwig and keto arylation.
These have all been carried out for the first time on free, unprotected halotryptophans, a challenging species known to coordinate to the catalyst.

Our new enzyme with a preference for iodination is game changing. It provides a powerful tool for C-H activation and diversification. It mediates the generation of C-I bonds (far more reactive than the C-Br, or C-Cl blonds), enabling the employment of even milder conditions.
We have developed culture conditions and media that are compatible with natural product generation, without inhibiting cross-coupling catalysis.

The project has let to several notable novel findings and unconventional methodologies, which have attracted press attention, namely:

- The first flavin dependent halogenase with a preference for iodination.
It is notably, also the first halogenase identified from a virus.
For C&EN highlight see:

- The identification of a sequence motif that can be used for mining for halogenase genes in silicons - the first motif enabling this definitive identification
(Prior motifs could not discriminate between halogenases and other flavin dependent enzymes).

- A unique and sustainable approach to photoprotection.
One of our test bed molecules was unstable too light.
This powerful antibiotic was precluded from development due to its poor photo-stability.
We developed a new and unconventional approach using pollen - and demonstrating remarkable photopotection.
An safe and sustainable approach that can potentially be used to rescue many medicinally relevant but photo unstable molecules.

This work resulted in considerable media coveragewas selected for the 2020 RSC desktop calendar

For interview with : Alan @kasujja #BBCNewsday @BBCworldservice click

For Times Review : © Royal Society of Chemistry