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BIOCATALYSIS

Challenging nature’s preference for methylation

Nature Chemistry volume 12, pages 791–792 (2020)Cite this article

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Enzymes that methylate using S-adenosyl-l-methionine — nature’s methyliodide — are abundant and often promiscuous; however, a preference for alkylation over methylation has been neither observed in nature nor engineered. Now, carboxymethylation has been demonstrated using engineered methyltransferases.

In nature, carboxy-SAM is used in very specific cases for the carboxymethylation of natural products. It was discovered in the biosynthesis of the modified RNA base 5-oxyacetyl uridine, at the ‘wobble’ position of bacterial transfer RNAs5. Later, carboxy-SAM was reported to be involved in the biosynthesis of 3-thiaglutamate, a glutamate isostere with a yet-to-be-elucidated function6. Carboxy-SAM is produced by a carboxy-SAM synthase using SAM and prephenate (Fig. 1b) and occurs via an unusual SAM ylide intermediate. The corresponding carboxymethyl transferases efficiently discriminate carboxy-SAM against the much more abundant SAM to avoid accidental methylation of the substrate. The Micklefield group set out to impose this inherent carboxymethylation preference on MTases as a strategy for the development of an orthogonal system.

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Fig. 1: Enzymatic alkylation, carboxymethylation and carboxyalkylation.

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Authors and Affiliations

  1. Institute of Pharmaceutical Sciences, University of Freiburg, Freiburg im Breisgau, Germany

    Jennifer N. Andexer

  2. Institute of Biochemistry, University of Münster, Münster, Germany

    Andrea Rentmeister

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  1. Jennifer N. Andexer
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  2. Andrea Rentmeister
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Correspondence to Jennifer N. Andexer or Andrea Rentmeister.

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Andexer, J.N., Rentmeister, A. Challenging nature’s preference for methylation. Nat. Chem. 12, 791–792 (2020). https://doi.org/10.1038/s41557-020-0533-1

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