Biocatalysis may provide a more sustainable approach to making complex molecules than traditional chemical synthesis. As the discovery of novel enzyme classes progresses, the biocatalytic toolbox is becoming more comprehensive, suggesting that enzyme-based synthesis of complex artificial molecules is becoming a realistic perspective for industrial production. Enzymes that catalyze group-transfer reactions depend on complex co-substrates – such as S-adenosylmethionine-dependent methyltransferases (SAM) – which must be regenerated after every turnover. This dependence makes the application of methyltransferases for preparative reactions difficult. In this project we showed this this problem can be circumvented by introducing a robust cofactor-regeneration system. As a proof-of-concept we developed and optimized enzyme-catalyzed cascade reactions that enable the one-pot synthesis of natural products and non-natural derivatives thereof.
