Page 424 - Cascade_Biocatalysis_Integrating_Stereoselective_and_Environmentally_Friendly_Reactions

400 18 Methyltransferases in Biocatalysis

HO NH 2 H 3 CO NH 2
SAM
COMT
HO HO
5 6

Scheme 18.3 Dopamine methylation catalyzed by COMT.
Small-molecule MTs are involved in the biosynthesis of bioactive compounds
such as neurotransmitters (e.g., dopamine) or antibiotics. COMT is the most promi-
nent and most intensively investigated MT among the enzymes acting on small
molecules. The methylation of one of the two phenolic hydroxyl groups of dopamine
5 is the first step in the biodegradation of neurotransmitters (Scheme 18.3).
COMT has been subjected to intensive pharmacological investigations in order to
develop therapeutic routes for the treatment of neurodegenerative diseases such as
Parkinson’s [25].
DNA methylation is a control mechanism in epigenetics. In mammals, only
DNA methylation at C5-position of cytosine has been found, while in bacteria and
archaea also N4-cytosine and N6-adenine methylations are known.
RNA methylation modulates the interactions of rRNA, tRNA, mRNA, snRNA
(small nuclear ribonucleic acid), proteins, or ligands within the ribosome. The
′
methylation of RNA takes place either on the 2 -OH of ribose or at the nucleobases
with higher diversity than DNA methylation [26].
Protein methylation takes place at the N-atoms of arginine or lysine residues
or O-atoms of carboxyl groups of glutamate or isoaspartate or C-terminal carboxyl
groups, and is involved in protein repair and sorting, signal transduction, and also
regulation of gene expression [27].
An important reason for the application of MTs in biocatalysis is the selectivity
advantage of enzymatic reactions. Intensive research and investigations on DNA
and protein MTs have led to impressive results and valuable applications of these
specific MTs [28].

18.2.2
Cofactors

The methyl group in SAM 1 has been described in the literature as a ‘‘natural
methyl iodide’’ [29]. It acts as an electrophile and facilitates S 2 reactions. In
N
the methyl transfer reaction, the methyl group of SAM 1 is transferred to the
substrate catalyzed by a MT resulting in a methylated product and the thioether
S-adenosyl-l-homocysteine (SAH) 2, which is much more stable than the sulfonium
compound (Scheme 18.4). The sulfonium center is chiral as a result of three
different substituents and the electron lone pair at sulfur.
The biosynthesis of SAM 1 is catalyzed by S-adenosylmethionine synthetase
(also called methionine adenosyltransferase, MTA), where l-Met 7 and adenine
triphosphate (ATP) are substrates to result in SAM and inorganic phosphate (P )
i
and inorganic pyrophosphate (PP ) (Scheme 18.5, pathway i). The hydrolysis of the
i