Quantification of N-acetylcysteamine activated methylmalonate incorporation into polyketide biosynthesis

Quantification of N-acetylcysteamine activated methylmalonate incorporation into polyketide biosynthesis

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Polyketides are biosynthesized through consecutive decarboxylative Claisen condensations between a carboxylic acid and differently substituted malonic acid thioesters, both tethered to the giant polyketide synthase enzymes.Individual malonic acid derivatives Holiday Decorations are typically required to be activated as coenzyme A-thioesters prior to their enzyme-catalyzed transfer onto the polyketide synthase.Control over the selection of malonic acid building blocks promises great potential for the experimental alteration of polyketide structure and bioactivity.One requirement for this endeavor is the supplementation of the bacterial polyketide fermentation system with tailored synthetic thioester-activated malonates.

The membrane permeable N-acetylcysteamine has been proposed as a coenzyme A-mimic for this purpose.Here, the incorporation efficiency Frosted Lantern into different polyketides of N-acetylcysteamine activated methylmalonate is studied and quantified, showing a surprisingly high and transferable activity of these polyketide synthase substrate analogues in vivo.