Oxidative Metabolism

Question 1

Pyruvate Kinase Deficiency

Answer 1

• Rarely seen genetic defect of glycolysis (1/20,000 of Northern European descent)
• Effects the erythrocyte-specific isozyme of pyruvate kinase
• May severely limit Erythrocyte ATP synthesis
• Causes hemolytic anemia (RBC lysis)

Question 2

Pyruvate dehydrogenase deficiency

Answer 2

• accumulation of pyruvate, lactate, alanine; neurological defects, severe or even lethal, depending upon the degree of impairment in enzyme activity

Question 3

Fumarase deficiency

Answer 3

symptom is abnormally high excretion of fumarate or other TCA cycle intermediates in urine. Both developmental and neurological defects are seen.
Although rare, this is the most prevalent mutation of TCA cycle enzyme. In recent years, a number of fumarase-deficient patients were identified in a SW Utah community.
Mutations in succinyl CoA synthetase have also been described.

Question 4

Vitamin deficiency

Answer 4

niacin (NAD), thiamine (TPP), riboflavin (FAD), pantothenic acid (Coenzyme A) affect the activity of pyruvate DH and TCA enzymes

Note: Beriberi (thiamine deficiency) mimics PDH deficiency

Question 5

Arsenic poisoning

Answer 5

The PDH complex is subject to irreversible inhibition by arsenite (AsO2-), which binds tightly to the -SH group of lipoic acid, rapidly inhibiting the oxidation of pyruvate.
Lipoic acid is also a component of the TCA cycle enzyme a-ketoglutarate dehydrogenase.

Question 6

Cyanide poisoning

Answer 6

CN- binds to heme of cytochrome a3, causes extremely rapid shutdown of the ETS, stops respiration

Question 7

FIAU (fialuridine) toxicity

Answer 7

FIAU once tried as anti-viral drug (hepatitis); however, lactic acidosis resulted from inhibition of the mitochondrial DNA polymerase by this uridine analog

Question 8

Mitochondrial respiratory-chain diseases

Answer 8

Several mutations in mitochondrial DNA (mtDNA) have been linked to ETS defects.
An example is Leber’s hereditary optic neuropathy (LHON), a neurodegenerative disease resulting from a mutation in the NADH-ubiquinone oxidoreductase of Complex I, which is encoded by mtDNA.
Muscle defects due to mitochondrial mutations are called “mitochondrial myopathies”
At least a dozen mtDNA mutations have been associated with disease, affecting CNS, cardiac muscle, kidney, gastrointestinal and endocrine function.

Question 9

Complex 1 poisoning

Answer 9

Rotenone and amytal

Question 10

Complex 2 poisoning

Answer 10

Antimycin A

Question 11

Complex 3 poisoning

Answer 11

CN, azide (N3-), CO-

Inhibitors bind to heme-Fe in cytochromes a and a2, and prevent binding of oxygen

Question 12

2,4-dinitrophenol and pentachlorophenol

Answer 12

Citrate - formation of acetyl CoA for synthesis of
fatty acids, sterols
a-ketoglutarate - formation of glutamate, glutamine
Succinyl CoA - porphyrin (heme) synthesis
Oxaloacetate – aspartate, asparagine, nucleotides
carbohydrate synthesis (gluconeogenesis

Question 13

Thermogenin protein

Answer 13

(UCP-1, uncoupling protein) in mitochondria of brown fat* is also a ETS uncoupler (there are at least 4 more UCP isoforms, whose function is not as well understood) *important for temperature regulation in newborns/infants

Question 14

Valinomycin

Answer 14

transports K+ instead of H+

Question 15

Oligomycin

Answer 15

inhibits the ATP synthase/ ATPase by blocking proton flow