A 35-year-old man comes to the office with progressively worsening fatigue associated with dark urine and back pain. Two days ago, the patient ate some large, flat beans brought home by his wife after a business trip to Egypt. Physical examination shows jaundice and pallor. Laboratory results reveal a hemoglobin level of 8 g/dL. Further evaluation reveals deficiency of an enzyme involved in the conversion of glucose-6-phosphate to ribulose-5-phosphate. The substance generated during this conversion is necessary for which of the following biochemical processes?
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This patient most likely has glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD catalyzes the first step in the pentose phosphate pathway (PPP), the oxidative portion of which generates 2 molecules of NADPH while converting glucose-6-phosphate to ribulose-5-phosphate. The nonoxidative reactions of the PPP reversibly convert ribulose-5-phosphate into ribose-5-phosphate (substrate for nucleotide synthesis) or glycolytic intermediates that can be used for energy production.
Because the PPP is the main source of NADPH, the pathway is particularly active in:
Cells experiencing high oxidative stress (eg, erythrocytes) in which NADPH is used to regenerate reduced glutathione, an antioxidant that helps maintain cell integrity
Organs such as the liver and adrenal cortex that are involved in reductive biosynthesis (eg, synthesis of fatty acids, cholesterol, steroids) and cytochrome P450 metabolism
Phagocytic cells generating a respiratory burst via NADPH oxidase
In patients with G6PD deficiency, erythrocytes are unable to maintain a sufficient supply of reduced glutathione during periods of increased oxidative stress, which can occur with certain infections (eg, pneumonia, viral hepatitis), consumption of fava beans, or specific medications (eg, primaquine, sulfa drugs). The resulting oxidative damage causes acute hemolytic anemia and jaundice.
(Choice A) NADH can be used as a reducing agent to convert ADP to ATP during oxidative phosphorylation. In contrast to NADH, NADPH cannot be used to convert ADP into ATP.
(Choice C) Glycogenesis is the process by which glucose is stored for later use through the addition of glucose molecules to glycogen chains. It does not require NADPH.
(Choice D) Ketone bodies are formed mainly in the liver during times of fasting when there is increased fat degradation. Cytosolic HMG-CoA synthase is the starting point of cholesterol synthesis whereas the mitochondrial version of the enzyme is the rate-limiting step in ketone body synthesis. Unlike cholesterol synthesis, ketone body production does not require NADPH.
(Choice E) Protein catabolism begins with the hydrolysis of polypeptides into amino acids. These subsequently undergo transamination reactions that funnel the amine nitrogen predominately into glutamate, which is oxidatively deaminated to produce ammonia. The urea cycle then converts ammonia into urea for elimination in the urine.
Educational objective:
Glucose-6-phosphate dehydrogenase is the rate-limiting enzyme in the pentose phosphate pathway, the major source of cellular NADPH. This molecule is necessary for reducing glutathione (protects red blood cells from oxidative damage) and for the biosynthesis of cholesterol, fatty acids, and steroids.