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134 Chapter 6
Inactivation by tranylcypromine
Ph
FAD
FADH
H
Ph
SEnz
SEnz
SEnz
NH 2
NH 2
+
Ph
+ +
NH 2 Ph NH 2
FADH 2
Possible reaction mechanisms
R
route a
NH 2
1e − transfer R
+
NH 2
H transfer R
FAD FADH
FADH FADH 2
+ H + deprotonation route b
1e − transfer
NH 2
+
FADH 2
imine
hydrolysis
FADH + H +
R
O
+ NH 4
+
R
+
NH 2
R
NH 2
Figure 6.18 Monoamine oxidase inactivation and reaction mechanisms.
Thus, both the Xavin-dependent dehydrogenases and oxidases appear to
follow radical mechanisms involving single electron transfers to Xavin. In the
case of the amine oxidases, there is good chemical precedent for this type of
mechanism in the form of electrochemical single electron oxidation of amines to
the corresponding imines. Similar radical mechanisms can be written for succinate
dehydrogenase and d-amino acid oxidase. Note that in acyl CoA dehydrogenase
deprotonation occurs adjacent to a thioester carbonyl to form a
stabilised enolate anion, whereas in succinate dehydrogenase deprotonation
would occur adjacent to a carboxylate anion. As discussed in Section 7.3, a
proton adjacent to an ester or a carboxylic acid is much less acidic than
a proton adjacent to a ketone or thioester. The mechanism by which this
problem is resolved is not well understood, but may involve protonation of
the carboxylate and/or electrostatic stabilisation of the carbanion intermediate.
This issue is also relevant to the cofactor-independent amino acid racemases
which will be discussed in Section 10.2.
6.4 Flavin-dependent mono-oxygenases
The ability of Xavin to react with molecular oxygen, seen above with the
oxidases, also makes possible a number of mono-oxygenase reactions, in
which one atom from molecular oxygen is incorporated into the product. The
most common Xavin-dependent mono-oxygenases are the phenolic hydroxylases,
in which a hydroxyl group is inserted into the ortho-orpara- position of a
phenol (or aniline). As in the Xavin-dependent oxidases, oxygen reacts with