Introduction to Enzyme and Coenzyme Chemistry - E-Library Home

Enzymatic Hydrolysis and Group Transfer Reactions 113
methyl group from Nature’s methyl group donor – S-adenosyl methionine
(SAM). The methyl group to be transferred is attached to a positively charged
sulphur atom, which is a very good leaving group for such a methylation
reaction. Analysis of such methyltransferase reactions using the chiral methyl
group approach detailed in Section 4.4 has revealed that they proceed with
inversion of stereochemistry, implying that the reaction is a straightforward
S N 2 displacement reaction (see Figure 5.41).
R
O
H
+
H 3 N
NH 2
NH 2
N N
N
H 3 C
N
+
R O CH 3
S N
methyltransferase
N
O
S N
N
O
CO −
H 3 N +
2 HO OH
CO
−
2 HO OH
S-adenosyl methionine
S-adenosyl homocysteine
Figure 5.41 Methyl group transfer from S-adenosyl methionine.
As well as oxygen and nitrogen nucleophiles, SAM-dependent methyltransferases
also operate on stabilised carbon nucleophiles, providing many of the
methyl groups found in polyketide natural products, and in the structure of
vitamin B 12 (see Section 11.2). The by-product of methyltransferase enzymes is
S-adenosyl homocysteine, which is recycled to SAM via hydrolysis to adenosine
and homocysteine. How is the structure of S-adenosyl methionine assembled It
is synthesised from methionine and ATP by a very unusual displacement of
triphosphate, which is subsequently hydrolysed to phosphate and pyrophosphate
as shown in Figure 5.42.
As well as transferring methyl groups, Nature is able to transfer methylene
(2CH 2 2) groups and even methyne (2CH5) groups using another cofactor –
tetrahydrofolate. Tetrahydrofolate is biosynthesised from folic acid, which is an
essential element of the human diet. The active part of the molecule as far as
one-carbon transfer is concerned are the two nitrogen atoms N 5 and N 10 .Itis
− O
−
CO 2
+
H 3 N
CH S 3
O − O − O −
N
P O P O P O N
O O O
O
NH 2
N
N
+
H 3 N
S-adenosyl methionine
synthase
CO 2
−
N
S + CH 3
O
N
NH 2
N
N
+
− O
O − O − O −
P O P O P O −
O O O
HO
OH
HO
OH
− O
O −
P O
O
O −
P
O
O −
+
− O
O −
P O −
O
Figure 5.42 Biosynthesis of S-adenosyl methionine.