HEXOSE MONOPHOSPHATE SHUNT

HEXOSE MONOPHOSPHATE SHUNT

• What are the substrates for the pentose/hexose phosphate or hexose monophosphate (HMP) shunt?

• Glucose-6-phosphate and nicotinamide adenine dinucleotide phosphate (NADP+)

• Where in the cell does the HMP shunt occur?

• What organs in the body have extensive HMP shunt activity?

• Lactating mammary glands, liver, adrenal cortex (erythrocytes also have HMP shunt activity)

• What characteristic do these organs share?

• Sites of fatty acid or steroid synthesis

• What is the rate-limiting enzyme in the HMP shunt?

• Glucose-6-phosphate dehydrogenase (G6PD)

• Name an activator of the G6PD enzyme:

• Name an inhibitor of the G6PD enzyme:

• What are the major products of the HMP shunt?

• Ribose-5-phosphate and NADPH

• In what process is ribose-5-phosphate utilized?

• In nucleotide synthesis

• List three important processes which utilize NADPH:

• Anabolic processes (as a source of reducing equivalents)
• 2. Respiratory/oxidative burst—rapid release of reactive oxygen species by cells (e.g., by immune cells to fight bacteria)
• 3. Hepatic P-450 function

• How do RBCs utilize NADPH?

• Via the glutathione reductase enzyme to reduce glutathione

• List four important processes which utilize glutathione:

• Reduction of protein sulfhydryl groups
• Reduction of peroxidases
• Maintenance of reduced hemoglobin (Hgb)
• “Catching” amino acids in the extracellular space (via γ- glutamyltranspeptidase)

• Why are RBCs particularly vulnerable to oxidative damage?

• RBCs have the capacity to carry large amounts of O2 and are thus prone to oxidative damage because they have no ETC to reduce O2.

• What type of oxidative damage can occur to the hemoglobin in RBCs?

• In the presence of reaction oxygen species (ROS), hemoglobin may precipitate to form Heinz bodies.

• Heinz bodies are the histological hallmark of what disorder?

• G6PD deficiency

• What type of oxidative damage can occur to the plasma membranes of G6PD-deficient RBCs?

• Peroxidation → membrane weakness → hemolytic anemia

• What is the pathophysiology behind the symptoms of G6PD deficiency?

• With deficient G6PD, NADPH is not regenerated, which leads to a decrease in NADPH and increase in NADP+. Thus, less reduced glutathione is available to detoxify free radicals and peroxides. This results in the body’s RBCs having a poorer defense against oxidizing agents, which leads to hemolytic anemia.

• In what situations would oxidative damage in the presence of G6PD deficiency be accelerated?

• Ingestion of foods containing oxidants (i.e., fava beans)
• Treatment with certain drugs (i.e., sulfonamides, antituberculosis drugs)
• Infections (i.e., pneumonia, infectious hepatitis)

• Are males or females more likely to present with G6PD deficiency?

• Males (X-linked recessive disorder)

• How do polymorphonuclear leukocytes (PMNs) utilize NADPH?

• NADPH is used by NADPH oxidase to produce ROS that destroy bacteria.

• What is the most common cause of chronic granulomatous disease (CGD)?

• NADPH oxidase deficiency in PMNs

• What are the clinical manifestations of CGD?

• Increased susceptibility to infection by catalase-positive organisms such as Escherichia coli, Staphylococcus aureus, and Klebsiella; increased risk of lymphoma

• How do hepatocytes utilize NADPH?

• In the biosynthesis of fatty acids, cholesterol, and nucleotides

• Describe the pathogenesis of alcohol-induced hepatic steatosis:
• Alcohol metabolism disrupts the NADH/NAD+ ratio which prevents the utilization of glycerol-3-phosphate as a gluconeogenic substrate while increasing its diversion into triglycerides, resulting in hepatic steatosis.