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Multienzyme one-pot cascades incorporating methyltransferases for the strategic diversification of tetrahydroisoquinoline alkaloids

Subrizi, Fabiana, Wang, Yu, Thair, Benjamin, Méndez-Sánchez, Daniel, Roddan, Rebbeca, Cárdenas-Fernández, Max, Siegrist, Jutta, Richter, Micheal, Andexer, Jennifer, Ward, John and Hailes, Helen 2021. Multienzyme one-pot cascades incorporating methyltransferases for the strategic diversification of tetrahydroisoquinoline alkaloids. Angewandte Chemie International Edition 60 (34) , pp. 18673-18679. 10.1002/anie.202104476

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The tetrahydroisoquinoline (THIQ) ring system is present in a large variety of structurally diverse natural products exhibiting a wide range of biological activities. Routes to mimic the biosynthetic pathways to such alkaloids, by building cascade reactions in vitro, represents a successful strategy and can offer better stereoselectivities than traditional synthetic methods. S-Adenosylmethionine (SAM)-dependent methyltransferases are crucial in the biosynthesis and diversification of THIQs; however, their application is often limited in vitro by the high cost of SAM and low substrate scope. In this study, we describe the use of methyltransferases in vitro in multi-enzyme cascades, including for the generation of SAM in situ. Up to seven enzymes were used for the regioselective diversification of natural and non-natural THIQs on an enzymatic preparative scale. Regioselectivites of the methyltransferases were dependent on the group at C-1 and presence of fluorine in the THIQs. An interesting dual activity was also discovered for the catechol methyltransferases used, which were found to be able to regioselectively methylate two different catechols in a single molecule.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Additional Information: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Publisher: Wiley
ISSN: 1521-3773
Date of First Compliant Deposit: 10 August 2021
Date of Acceptance: 8 June 2021
Last Modified: 14 Sep 2021 13:39

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