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176 Chapter 7
7.8 Thiamine pyrophosphate-dependent enzymes
Decarboxylation reactions are also widely found in biological chemistry. In
Chapter 3 we saw an example of the decarboxylation of a b-keto acid acetoacetate
by the action of acetoacetate decarboxylase, via an imine linkage. In
general terms b-keto acids can be fairly readily decarboxylated since the b-keto
group provides an electron sink for the decarboxylation reaction. No such
electron sink exists for a-keto acids; however, Nature has found a way of
decarboxylating a-keto acids, and in many cases forming a carbon–carbon
bond at the same time, using the coenzyme thiamine pyrophosphate (TPP).
Thiamine pyrophosphate is formed by phosphorylation of the vitamin
thiamine, lack of which causes the deWciency disease beri-beri. The structure
of TPP consists of two heterocyclic rings: a substituted pyrimidine ring and a
substituted thiazolium ring (see Figure 7.25). The thiazolium ring is responsible
for the catalytic chemistry carried out by this coenzyme, due to two chemical
properties:
(1) the acidity of the proton attached to the thiazolium ring;
(2) the presence of a carbon–nitrogen double bond that can act as an electron
sink for decarboxylation.
The decarboxylation of pyruvic acid is carried out by several TPP-dependent
enzymes, yielding acetaldehyde, acetic acid, acetyl CoA or a-hydroxyacetyl
compounds. Each of these products is formed via closely related mechanisms.
O
H
TPP
O
CO 2
−
TPP, RCHO
O
R
O
TPP
FAD,O 2
TPP
lipoamide, CoASH
O
OH
O −
SCoA
Thiamine pyrophosphate (TPP)
Lipoamide
OPP
O
N
+
N
S
S
S N Lys-Enz
H
N
NH 2
H
N-4'
C-2 exchanges with D 2 O at pH 7
Figure 7.25 Thiamine pyrophosphate-dependent reactions of pyruvate.