Development of PKS biocatalysts on the example of a multi-enzyme cascade for improved synthesis of antifungal polyketides

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This project aims to advance the establishment of polyketide synthase (PKS) modules as biocatalysts and to demonstrate the advantages of their use in the total synthesis of natural products. As an example, a multi-enzyme cascade is to be developed, with the PKS module AmbMod4 from the ambruticin biosynthesis at its centre. A tailor-made adaptation of the conditions should enable an optimal interaction of the module with the other enzymatic components. This cascade will find a concrete application in the context of the chemoenzymatic total synthesis of jerangolides. There, it is intended to replace the multi-step, synthetically difficult formation of a vinyltetrahydropyran by an efficient one-pot process, thereby significantly shortening the longest linear sequence. In order to establish the enzyme cascade, the production of AmbMod4 will be optimized and a suitable thioesterase domain will be identified which selectively releases the desired AmbMod4 product while avoiding conceivable side reactions. This would enable preparative biocatalytic reactions with AmbMod4. This cascade is to be gradually extended by a C-methyltransferase and a cyclase and scaled up to the semi-preparative scale.