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18
Methyltransferases in Biocatalysis

Ludger Wessjohann, Martin Dippe, Martin Tengg, and Mandana Gruber-Khadjawi

18.1
Introduction

The addition of a methyl group to an acceptor atom (usually a nucleophilic O, S, N,
or C) constitutes a crucial process in the surface decoration and functionalization of
natural products in all living organisms [1]. Methylation provides a biomolecule with
the specific properties required to perform its function in the native environment
but also in human applications. The emerging importance of DNA methylation
for (human) epigenetics is incontestable. The omission or addition of a methyl
group, formally the insertion of a methylene unit, though minor as it appears,
can change the biological properties significantly from 100% to 0% or vice versa
(Figure 18.1) [2]. But also subtle changes can result from methylation: for example,
increasing methylation in tocopherols and -trienols α to δ leads to increasing
reductive (antioxidative) power [3].
The chemical consequences of a methylation can be (i) an Umpolung and
lipophilization, for example, of hydroxyl, sulfhydryl, or amino groups, to enhance
protein binding and membrane permeation; (ii) an augmentation of electron
density to alter electronic properties, for example, by the methylation of aromatic
rings in (hydro)quinones such as vitamin E; (iii) the introduction of steric bulk or
constraint to enhance a specific conformation, binding interaction, or reactivity,
forexample,the synthesisof tert-butyl or cyclopropane moieties in steroids; and
(iv) the – partially reversible – selective protection and labeling of biomolecules,
for example, of information- and signal-carrying biopolymers such as DNA or
proteins. The authors estimate that roughly half of the natural products used
for medicinal or related applications, such as alkaloids or flavonoids, at some
stage in their (bio)synthesis require a methylation step. Considering the immense
importance of methylation reactions in both small natural product biosynthesis
and cellular regulation, it becomes evident that selective methylation has found
and increasingly will find its way into biocatalytic production processes and other
biotransformations.
To impose specific properties, natural methylation has to be selective, that is, in
most cases chemo- and regioselective, more rarely diastereo- and enantioselective.

Cascade Biocatalysis: Integrating Stereoselective and Environmentally Friendly Reactions, First Edition.
Edited by Sergio Riva and Wolf-Dieter Fessner.
c 2014 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2014 by Wiley-VCH Verlag GmbH & Co. KGaA.