Methyltransferases: Functions and Applications

Abstract

In this review the current state-of-the-art of S-adenosylmethionine (SAM)-dependent methyltransferases and SAM are evaluated. Their structural classification and diversity is introduced and key mechanistic aspects presented which are then detailed further. Then, catalytic SAM as a target for drugs, and approaches to utilise SAM as a cofactor in synthesis are introduced with different supply and regeneration approaches evaluated. The use of SAM analogues are also described. Finally O-, N-, C- and S-MTs, their synthetic applications and potential for compound diversification is given.

Keywords: S-adenosyl-l-methionine; biocatalysis; enzymes; methyltransferases.

Scheme 1

SAM‐dependent methyltransferases (MTs) have many potential applications in synthesis (SAH: S‐adenosylhomocysteine).

Figure 1

Representative structures for the known classes of methyltransferase. PDB codes: A – 6LFE (catechol‐O‐methyltransferase); B – 1MSK (methionine synthase, reactivation domain); C – 1CBF (cobalt precorrin‐4‐methyltransferase); D – 1MXI (tRNA (cytidine(34)‐2’‐O)‐methyltransferase); E – 1O9S (SET7/9); F – 3RFA (RlmN); G – 5VG9 (isoprenylcysteine carboxyl methyltransferase); H – 2NV4 (AF0241); I – 1TLJ (Taw3). Secondary structures represented within the molecular surface as cartoons, coloured by B factor: blue (high) to red (low) for α‐helices, the reverse for β‐sheets. Cofactor represented as magenta sticks. For E (1O9S), histone peptide represented as blue sticks. For F (3RFA), iron‐sulfur cluster represented as spheres.

Figure 2

The proximity and desolvation mechanism of DnrK (PDB ID: 1TW2) enables the selective methylation in the daunorubicin biosynthesis.

Figure 3

Active site of NirE with Arg111 as base for the protonation of the substrate. Hydrogen bonds between the SAH and the protein due to Met186 help to keep the two reacting molecules in place (PDB ID: 2YBQ).

Figure 4

Metal‐dependent methylation catalysis mechanism for A) CCoAOMT (PDB ID: 1SUI) and B) Mycinamicin VI in the active site of MycE (PDB ID: 3SSN).

Figure 5

CFASs catalyses the formation of cyclopropane where carbonate ion is coordinated with labelled residues. The carbonate also acts as base (PDB ID: 6BQC).

Figure 6

SAM modification on the alkyl group (blue), amino acid (yellow), sugar (orange), nucleobase (green) and replacement of the sulfur atom (red).

Scheme 2

General strategy for protein methylation by NTMT. Protein N‐terminal methyltransferases (NTMTs) catalyse the transfer of methyl group from S‐adenosylmethionine (SAM) to the α‐amino group at the protein N‐terminus.

Figure 7

Enzymatic systems for SAM supply and regeneration. A. Cyclic regeneration system using seven enzymes starting from catalytic amounts of AMP and methionine. B. Linear enzyme cascades starting either from ATP and methionine or from ClDA/FDA and methionine. C. Two enzyme regeneration system starting from SAH. Enzymes: MAT=l‐methionine adenosyltransferase; MT=methyltransferase; MTAN=5’‐methylthioadenosine/S‐adenosyl‐l‐homocysteine nucleosidase; SAHH=S‐adenosyl‐l‐homocysteine hydrolase; ADK= adenosine kinase; PPK= polyphosphate kinase; HSMT=l‐homocysteine S‐methyltransferase: HMT=halide methyltransferase SalL=chlorinase FDAS=fluorinase. Substrates: ATP/ADP/AMP=adenosine 5’‐tri/di/monophosphate; Met=l‐methionine; SMM=S‐methyl‐l‐methionine; SAM=S‐adenosyl‐l‐methionine; SAH=S‐adenosyl‐l‐homocysteine. ClDA=5’‐chloro‐5’‐deoxyadenosine. FDA= 5’‐deoxy‐5’‐fluoroadenosine.

Figure 8

The regiospecific alkylation reaction for COMT.

Figure 9

O‐Methyl transferases (OMTs) as catalysts are involved in the biosynthesis of aromatic compounds.

Figure 10

Examples for drug targets in the pharmaceutical industry: products of O‐methyl transferases (OMTs) catalysed reactions.

Figure 11

Examples for pharmaceuticals compounds: products of N‐methyltransferases (NMTs) catalysed reactions.

Figure 12

Examples for pharmaceuticals compounds: products of C‐methyltransferases (CMTs) catalysed reactions.