Étude multidisciplinaire des aspects clés de la biosynthèse des polykétides par des polykétide synthases modulaires

Abstract : Polyketides are natural products which exhibit a variety of therapeutic activities, including anti-fungal, antibiotic, anticancer, immunosuppressant and anti-cholesterolemic properties. Given their medical and economic importance, there is significant interest in identifying new structures with new biological activities. A promising strategy to create such analogues is to genetically engineer the enzymes responsible for synthesizing these molecules, the modular polyketide synthases (PKSs), an approach referred to as ‘synthetic biology’. However, in order to increase the efficacy of this approach, we must understand in detail how the PKS multienzymes work. A number of issues remain to be clarified, including: i) polyketide stereocontrol, ii) the interaction of the component subunits PKS. During my thesis, I identified two ketoreductase (KR) domains which when introduced into an intrinsically non-epimerizing modular context, were able to efficiently epimerise at the C[alpha] of a model polyketide. I also showed that the modular context in which the KR functions has an influence on the ultimate stereochemical outcome. I also made essential contributions to a second project, in which the group identified a novel family of docking domains (DD) in the trans-AT type of PKS which present a novel topology. One of the two model DDs studied is an intrinsically disordered protein whose folding is induced by its partner. Finally, we were able to visualize a complete intersubunit interface within a trans-AT PKS, revealing a protected reaction center in which polyketide chains can grow.
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Thibault Annaval. Étude multidisciplinaire des aspects clés de la biosynthèse des polykétides par des polykétide synthases modulaires. Biochimie, Biologie Moléculaire. Université de Lorraine, 2015. Français. ⟨NNT : 2015LORR0241⟩. ⟨tel-01754505⟩

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