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?
- Cytoplasm
- 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:
- NADP+
- Name an inhibitor of the G6PD enzyme:
- NADPH
- 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.
