S-Adenosylmethionine (SAM)-dependent enzymes have great potential for selective alkylation processes. In this study we investigated the regiocomplementary O-methylation of catechols. Enzymatic methylation is often hampered by the need for a stoichiometric supply of SAM and the inhibitory effect of the SAM-derived byproduct on most methyltransferases. To counteract these issues we set up an enzyme cascade. Firstly, SAM was generated from l-methionine and ATP by use of an archaeal methionine adenosyltransferase. Secondly, 4-O-methylation of the substrates dopamine and dihydrocaffeic acid was achieved by use of SafC from the saframycin biosynthesis pathway in 40-70 % yield and high selectivity. The regiocomplementary 3-O-methylation was catalysed by catechol O-methyltransferase from rat. Thirdly, the beneficial influence of a nucleosidase on the overall conversion was demonstrated. The results of this study are important milestones on the pathway to catalytic SAM-dependent alkylation processes.
The back cover picture shows the three‐enzyme cascade for regiocomplementary O‐methylation of catechols. This cascade can be imagined as a jigsaw puzzle containing exchangeable pieces. The methyltransferase reaction is integrated in a cascade with an S‐adenosylmethionine‐generating methionine adenosyltransferase (cofactor supply) and a methylthioadenosine‐S‐adenosylhomocysteine nucleosidase (by‐product degradation). This system allows the combination of various enzymes and substrates. As a proof of concept, two regiocomplementary catechol‐O‐methyltransferases, which catalyse the reaction towards meta‐ or para‐methylated catechols, were applied. Both methyltransferases show a broad substrate range and give rise to a variety of building blocks.
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