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18.2 SAM-Dependent Methyltransferases 395

• Other processes toward the product which are not intrinsically connected to the
methyl transfer. Such reactions are not included here.
In this chapter, the basics of MT-catalyzed biotransformations will be reviewed,
including non-natural variations. Special emphasis is given to reactions connected
to preceding or subsequent steps as pointed out above. However, very few cascaded
in vitro processes have been reported so far, as current trends are more directed to
multistep in vivo biotransformations (metabolic engineering, synthetic biology).

18.2
SAM-Dependent Methyltransferases

SAM 1 (Figure 18.2) is the most widely used methyl donor in nature and was first
described by Cantoni in 1953 [5].
The enzymes that catalyze the transfer reaction of the methyl group are
called methyltransferases and are classified as EC 2.1.1.X. by the International
Union of Biochemistry and Molecular Biology (IUBMB: http://www.chem.
qmul.ac.uk/iubmb/enzyme/) [6]. The target substrates of these enzymes are very
diverse, ranging from small molecules to biopolymers such as DNA, RNA, lipids,
carbohydrates, or proteins. In DNA and proteins, sequence-specific methylations
are observed [7]. SAM-dependent MTs are also involved in the synthesis of
cyclopropane rings in nature, for example, of cyclopropane fatty acids or sterols [8,
9]. Astonishingly, even inorganic arsenite and halides [10] are substrates for MTs.
During the last decades, many investigations have been directed to clarify
structures and functions of SAM-dependent MTs and many of them have been
described so far [11]. SAM-dependent MTs are divided into five classes (I–V)
according to their structural fold [12]. Class I is the largest group among the SAM-
dependent MTs, showing high diversity in substrates and targets of methylation.
Class I MTs have a Rossman-like fold and show high structural consensus while
having only about 10% sequence similarity.
SAM can act as a radical source as well. The ‘‘radical-SAM’’ enzymes contain
an iron–sulfur cluster. The interaction of the cluster and SAM leads to radical
formation and catalysis. X-ray structure analysis of two radical SAM enzymes [13]
has led to a proposed mechanism that starts with binding of SAM via its amino
and carboxylate residues to the free coordination sites of iron, which is part of the

HOOC NH 2 NH 2
N
N
N N
H 3 C S
O
1
OH OH
Figure 18.2 S-Adenosyl-L-methionine (AdoMet or SAM).