Pentose Phosphate Pathway

  • The Pentose Phosphate Pathway (PPP) is crucial in cellular metabolism, specifically for generating NADPH and ribose-5-phosphate.

Clinical Case

  • Subject: 31-year-old black male, Peace Corps volunteer in Africa.

  • Symptoms: Complaints of weakness, fatigue, yellowing of the skin (jaundice), and slight fever.

  • Treatment History: Prescribed primaquine for malaria.

  • Lab Results:

    • Elevated indirect bilirubin.

    • Low hemoglobin and hematocrit.

    • Presence of spherocytes and Heinz bodies.

  • Reference: Swanson et al., Underground Clinical Vignettes, Biochemistry, 5e, Lippincott Williams & Wilkins.

Diagnosis

  • Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency:

    • Incidence: Approximately 25% in individuals of Mediterranean, tropical African, and (sub)tropical Asian descent.

    • Inheritance: X-linked recessive disorder.

    • Due to high incidence, many females are homozygous.

    • Majority of carriers remain asymptomatic throughout life.

    • Common Symptoms: Neonatal jaundice, acute hemolytic anemia.

    • Acute hemolysis may be the only clinical manifestation and can go undetected.

    • Reference: https://themedicalbiochemistrypage.org/glucose-6-phosphate-dehydrogenase-g6pd-deficiency/

Pentose Phosphate Pathway Functions

  • Primary Functions:

    1. Generate Reducing Equivalents (NADPH):

    • For reductive biosynthesis of cholesterol, bile acids, steroid hormones, and fatty acids.

    1. Regeneration of Reduced Glutathione (GSH):

    • Detoxifies hydrogen peroxide (H2O2).

    1. Synthesis of Ribose-5-Phosphate (R5P):

    • For nucleotide synthesis.

  • Also acts as an alternate glucose oxidation pathway.

  • Reference: Berg et al., Biochemistry, 9e, W.H. Freeman and Co.

NADPH

  • Forms:

    • Reduced form: Nicotinamide Adenosine Dinucleotide Phosphate (NADPH).

    • Oxidized form: NADP+.

  • Hub Role in Metabolism:

    • NADPH serves as a carrier of reducing power for anabolic pathways, unlike NADH, which is primarily used for ATP generation in catabolic pathways.

  • Reference: Salway, Medical Biochemistry at a Glance, 3e, Wiley-Blackwell.

NADPH Generating Steps

  • Key Reactions in PPP:

    • Glucose-6-phosphate → 6-Phosphoglucono-6-lactone (via glucose-6-phosphate dehydrogenase)

    • 6-Phosphoglucono-6-lactone → 6-Phosphogluconate (via lactonase)

    • 6-Phosphogluconate → Ribulose-5-phosphate (via 6-phosphogluconate dehydrogenase)

  • Reference: Berg et al., Biochemistry, 9e, W.H. Freeman and Co.

Liver Pentose Phosphate Pathway

  • Overview of the pathway's function in the liver.

  • Produces NADPH for biosynthetic reactions and routes fructose-6-phosphate through glycolysis for fatty acid synthesis.

Red Blood Cell Pentose Phosphate Pathway

  • Oxidative Stress:

    • Reactive oxygen species (ROS) are generated through various mechanisms, including electron leakage from the Electron Transport Chain (ETC).

    • In RBCs, ROS is produced via hemoglobin oxidation and can lead to cell lysis if not managed.

    • Reference: Berg et al., Biochemistry, 9e, W.H. Freeman and Co.

Glutathione

  • Role in Red Blood Cells:

    • Tripeptide with a sulfhydryl group (GSH) abundant in animal cells (approx. 5 mM).

    • Protects RBCs from oxidative damage by acting as a sulfhydryl buffer.

    • Function of Glutathione Peroxidase: Converts H2O2 to H2O by oxidizing GSH to GSSG.

  • Recycling of GSH is essential, using NADPH to reduce GSSG back to GSH.

  • Reference: Berg et al., Biochemistry, 9e, W.H. Freeman and Co.

Classifications of G6PD Enzyme Variants

  • WHO Classification:

    • Class I: Severe deficiency (less than 10% of normal enzyme activity).

    • Class II: Moderate deficiency (10% to 60% of normal).

    • Class III: Mild to none (variation and clinical significance characterizes it).

    • Class IV: Increased activity (more than 150% of normal), with no hemolysis.

  • Clinical Features:

    • Chronic hemolytic anemia and intermittent hemolysis based on genetic background.

Favism

  • Clinical Manifestation: Hemolytic anemia post ingestion of fava beans due to toxic compounds divicine and isouramil, leading to GSH oxidation.

  • Related to G6PD deficiency that can be triggered by certain drugs and dietary substances.

  • Reference: https://themedicalbiochemistrypage.org/glucose-6-phosphate-dehydrogenase-g6pd-deficiency/

Treatment of G6PD Deficiency

  • Management Strategies:

    • Withdrawal of triggering compounds (e.g., primaquine, fava beans, sulfonamides).

    • Hydration to avert renal failure due to hemoglobinuria.