Design of bioactive sesquiterpene-based chemical signals with enhanced stability

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We have previously extensively investigated the active site of terpene synthases by a combination of protein engineering and synthetic chemistry. From this work, we hypothesize that subtle alterations to this chemical space will allow the docking and catalytic conversion of analogues of the natural precursor farnesyl diphosphate (FDP), and lead rationally to the production of analogues of biologically active naturally-occurring sesquiterpenes.
Signalling between organisms via small lipophilic molecules (SLMs), e.g. pheromones and other semiochemicals, can have profound impacts on development and, for higher organisms including human and other animals, on behaviour. Our chemical ecology work shows that plant-produced sesquiterpenes can be semiochemicals that modify the behaviour of major world pests, such as aphid pests attacking arable crops and pests of livestock and human health. This includes the highly unstable and volatile sesquiterpene hydrocarbon (S)-germacrene D.
We will investigate the chemical space of (S)-germacrene D synthase (GDS) using a synthetic biology approach. Investigations will involve a combination of introducing FDP analogues to GDSs, active site modification of wild type GDS, and production of a library of (S)-germacrene D analogues with greater stability.

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