chapter 13
Carbohydrate Metabolism I: Glycolysis and TCA Cycle
FIGURE 13-11
Regulation of pyruvate dehydrogenase (PD) by inactivation and reactivation by a non-cAMP-dependent
phosphorylation-dephosphorylation cycle. Although PD kinase phosphorylâtes three specific seryl residues in the
a-subunit of PD, phosphorylation at any of these sites inactivates PD. The kinase and the phosphatase are under
the influence of several regulators, and the dephospho-active PD is also regulated by end products. ® = Activation;
= inhibition;
= dihydroiipoyl transacetylase; E
= dihydrolipoyl dehydrogenase.
in the active state.
In experimental animals and in
humans with lactic acidemia due to a variety of causes,
dichloroacetate administration lowers the concentration
of lactate through promotion of pyruvate oxidation. Com-
pounds like dichloroacetate have potential applications in
disorders associated with lactic acidemia (e.g., diabetes
Abnormalities o f Pyruvate Dehydrogenase Complex
Thiamine deficiency causes decreased pyruvate oxi-
dation, leading to accumulation of pyruvate and lactate,
particularly in the blood and brain, and is accompanied
by impairment of the cardiovascular, nervous, and gas-
trointestinal systems (Chapter 38). Inherited deficiency
of pyruvate dehydrogenase complex is accompanied by
lactic acidemia and abnormalities of the nervous sys-
tem (e.g., ataxia and psychomotor retardation). Pyruvate
(Chapter 15). Both inherited disorders of pyruvate utiliza-
tion are autosomal recessive.
Nervous system abnormalities may be attributed in part
to diminished synthesis of neurotransmitters rather than
to inadequate synthesis of ATP. In pyruvate dehydro-
genase complex deficiency, diminished levels of acetyl-
CoA cause decreased production of acetylcholine; in
pyruvate carboxylase deficiency, decreased production of
oxaloacetate may lead to deficiency of amino acid neuro-
transmitters (e.g., y-aminobutyrate, glutamate, aspartate).
The interrelationships of these amino acids are discussed
in Chapter 17. Although no particular therapeutic method
is well established in treatment of the inherited disor-
ders of pyruvate metabolism, ketogenic diets have been
beneficial in pyruvate dehydrogenase complex deficiency,
since they provide the product of the deficient reaction
(acetyl-CoA). Administration of large doses of thiamine
may be of benefit because mutations of pyruvate dehy-
drogenase complex may give rise to decreased affinity for
thiamine pyrophosphate. In one patient, administration of
dichloroacetate was beneficial even in the absence of a
ketogenic diet.
In pyruvate carboxylase deficiency, administration of
diets supplemented with aspartate and glutamate demon-
strated sustained improvement in neurological symptoms.
These two amino acids cross the blood-brain barrier af-
ter amidation to asparagine and glutamine in nonneural
tissues. The toxicity of organic arsenicals and arsenite
(AsOj_)is due to their abiltiy to bind functional sulfhydryl
groups of enzymes. One important target is the dithiol
form of the lipoyl group of pyruvate dehydrogenase and
a-ketoglutarate dehydrogenase complexes. In the earlier
times arsenicals were used in the treatment of syphilis,
however due to their toxicity it has been replaced with
better drugs such as penicillin.
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