section 13.2
Pyruvate Metabolism
239
Riboflavin
HÇOH
FIGURE 13-9
Flavin adenine dinucleotide (FAD).
chain, with the production of ATP (Chapter 14). Di-
hydrolipoyl transacetylase plays a central role in trans-
ferring hydrogen atoms and acetyl groups from one
enzyme to the next in the pyruvate dehydrogenase com-
plex. This is made possible by the lipoyl-lysyl swinging
arm of the transacetylase, which is about 1,4 nm long
(Figure 13-10).
In
a
similar
way,
other
a-keto
acids,
e.g.,
a-ketoglutaratc (in the TCA cycle; see below) and
branched-chain a-keto acids derived by transamination
from the branched-chain amino acids valine, leucine,
and isoleucine (Chapter 17), undergo decarboxylation
and dehydrogenation catalyzed by enzyme complexes.
These enzyme complexes differ in specificity of Ei
and E2, but all contain the same E
3
(the dihydrolipoyl
dehydrogenase).
Regulation o f Pyruvate Dehydrogenase Activity
The pyruvate dehydrogenase complex catalyzes an irre-
versible reaction that is the entry point of pyruvate into the
TCA cycle (see below) and is under complex regulation by
allosteric and covalent modification of the pyruvate dehy-
drogenase component of the complex. The end products
of the overall reaction (NADH and acetyl-CoA) are po-
tent allosteric inhibitors of the pyruvate dehydrogenase
FIGURE 13-10
Schematic representation of the relationship between the three enzymes of
the pyruvate dehydrogenase complex. The lipoyl-lysyl moiety of the
transacetylase delivers the acetyl group to CoA and the reducing
equivalents to FAD. TPP = Thiamine pyrophosphate.
component of the complex. They also function as effec-
tors in a non-cAMP-dependent reversible phosphorylation
and dephosphorylation cycle of the dehydrogenase. Phos-
phorylation occurs by an ATP-specific pyruvate dehydro-
genase kinase at three serine residues of the a-subunit of
the enzyme and leads to inactivation. The kinase is acti-
vated by elevated [acetyl-CoA]/[CoA], [NADH]/[NAD+],
and [ATP]/[ADP] and inhibited by increases in [pyruvate],
[Ca2+], and [K+], The phospho enzyme is converted to
the active dephospho enzyme by a pyruvate dehydroge-
nase phosphatase, an Mg
2
+/Ca2+-stimulated enzyme that
is also stimulated by insulin in adipocytes. The kinase and
phosphatase are associated with pyruvate dehydrogenase.
The regulation of pyruvate dehydrogenase is shown in
Figure
13-11. In general, when the levels of ATP,
NADH, or acetyl-CoA are high, the oxidation of pyru-
vate to acetyl-CoA is markedly decreased. For exam-
ple, fatty acid oxidation (Chapter 18) provides all three
metabolites and thus decreases the need for pyruvate
oxidation.
An
analogue
of
pyruvate,
dichloroacetate
(CHC
1 2
COO- ), inhibits pyruvate dehydrogenase kinase
and maintains the pyruvate dehydrogenase complex
