S‐Adenosyl‐Methionine‐Dependent Methyltransferases: Highly Versatile Enzymes in Biocatalysis, Biosynthesis and Other Biotechnological Applications

Abstract

S-adenosyl methionine (SAM) is a universal biological cofactor that is found in all branches of life where it plays a critical role in the transfer of methyl groups to various biomolecules, including DNA, proteins and small-molecule secondary metabolites. The methylation process thus has important implications in various disease processes and applications in industrial chemical processing. This methyl transfer is catalysed by SAM-dependent methyltransferases (MTases), which are by far the largest groups of SAM-dependent enzymes. A significant amount is now known regarding the structural biology and enzymology of these enzymes, and, consequently, there is now significant scope for the development of new MTases and SAM analogues for applications from biomolecular imaging to biocatalytic industrial processes. This review will focus on current efforts in the manipulation of class I and V SAM-dependent MTases and the use of synthetic SAM analogues, which together offer the best prospects for rational redesign towards biotechnological applications. Firstly, metabolic engineering of organisms incorporating small-molecule MTases is discussed; this can be applied in a variety of areas from the industrial bioprocessing of flavourants and antibiotics to frontier research in biofuel production and bioremediation. Secondly, the application of MTases in combination with SAM analogues is reviewed; this allows the tagging of proteins and oligonucleotides with moieties other than the methyl group. Such tagging allows the isolation of the tagged biomolecule and aids its visualisation by a range of analytical methods. The review then summarises the potential advantages of MTase-mediated chemistry and offers some future perspectives on downstream applications.

Functional Modification of Thioether Groups in Peptides, Polypeptides, and Proteins

“…14 These sulfonium salts, primarily S-adenosyl-L-methionine, abundant in animals, 14 and S-methyl-L-methionine, abundant in plants, 50 are stable molecules that are also marketed as nutritional supplements in many countries ( Figure 5). The first chemical synthesis of Met sulfonium salts, via reaction of Met with alkyl halides, was reported in the 1940s, 51,52 and was subsequently followed by alkylation reactions of Met residues in peptides, proteins, and polypeptides.…”

“…present in natural Met residues, has significant potential for use in functional modification and bioconjugation reactions. These methods build upon the rich biochemistry of Met, where its reversible alkylation and oxidation reactions are well known for their importance in enzyme catalyzed methyl transfer processes 14 and protection against oxidative protein damage, 15 respectively. This review article describes recent advances in selective chemical modification reactions on thioether groups in peptides, polypeptides and proteins, and the properties and potential applications of the resulting functionalized products.…”

Influence of Equatorial CH⋅⋅⋅O Interactions on Secondary Kinetic Isotope Effects for Methyl Transfer

“…Besides providing the prototypical example of an S N 2 mechanism, methyl transfer is an important component of many biological processes, not least in reactions mediated by AdoMet 4. In view of the small size of the methyl group, it is not obvious how an enzyme might preferentially stabilize the TS for methyl transfer relative to the reactant state (RS).…”

Methyltransferase‐Directed Labeling of Biomolecules and its Applications

“…The core element of this conserved fold consists of seven‐stranded β‐sheets with three helices on each side, a structural feature commonly referred to as the Rossman fold 2b, 41. This core is shared among MTases that act on all different substrates, ranging from small molecules to DNA and proteins 3, 42.…”

“…Because of their versatility, NP MTases, when used in combination with AdoMet or its artificial analogues, are particularly appealing in the context of biocatalysis and the production of fine chemicals, where they can help to unlock synthetic routes that would not be accessible using traditional methods. Excellent overviews of such efforts are provided elsewhere 2b, 66…”