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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;

E

2

= dihydroiipoyl transacetylase; E

3

= 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

mellitus).

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

carboxylase

deficiency

causes

similar

abnormalities

(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.