Pentose Phosphate Pathway

• The key glycolytic intermediates that branch off into other pathways are glucose 6 - phosphate, fructose 6 - phosphate, and dihydroxyacetone phosphate (DHAP).
• The Pentose Phosphate Pathway, also known as Pentose shunt, Hexose monophosphate shunt, Phosphogluconate pathway, occurs in the cytosol.
• The pathway begins with the glycolytic intermediate glucose 6 - P and reconnects with glycolysis because two of the end products of the pentose pathway are glyceraldehyde 3 - P and fructose 6 - P.
• The pathway yields reducing potential in the form of NADPH to be used in anabolic reactions requiring electrons and yields ribose 5 - phosphate for nucleotide biosynthesis.
• The pathway can be divided into two phases: non-oxidative interconversion of sugars and oxidative phase.
• NADPH + H + is formed from two separate reactions: the glucose 6 - phosphate DH (G6PD) reaction is the rate limiting step and is essentially irreversible.
• Cells have a greater need for NADPH than ribose 5 - phosphate.
• The nonoxidative phase of the pentose pathway entails extensive carbon atom rearrangement.
• Transketolase requires the coenzyme thiamine pyrophosphate (TPP), the transaldolase does not.
• Transketolase (TPP) and transaldolase are the link back to glycolysis.
• The growth of the malaria parasite, Plasmodium falciparum, fails in G6PD deficient individuals.
• Glutathione is essential for normal RBC structure and keeping hemoglobin in Fe ++ state.
• G6PD deficiency is also seen in Caucasians from the Mediterranean Basin.
• Individuals with reduced GSH are subject to hemolysis.
• The reduced form of glutathione serves as a sulfhydryl buffer.
• Conditions for hemolytic anemia related to G6PD deficiency include the ingestion of oxidative agents that generate peroxides or reactive oxygen species (ROS) and individuals with G6PD deficiency cannot produce sufficient GSH to cope with the ROS.
• Reduced glutathione also detoxifies peroxides.
• Reactive oxygen species (ROS) damage macromolecules (DNA, RNA, and protein) and ultimately lead to cell death.
• Proteins become cross linked leading to Heinz body formation and cell lysis in G6PD deficiency.
• The pentose pathway is linked to the supply of adequate amounts of GSH.
• The sulfhydryl of GSH is used to reduce peroxides (ROS) formed during oxygen transport.
• Glucose 6 - phosphate DH deficiency and nonspherocytic hemolytic anemia can be caused by over 300 genetic variants of the G6PD.
• Glutathione is extremely important particularly in the highly oxidizing environment of the red blood cell.
• As much as 10% of glucose consumption, by erythrocytes, is mediated by the pentose pathway.
• Insufficient production of NADPH due to glucose 6 - phosphate DH deficiency results in insufficient glutathione.
• The resulting oxidized form of GSH is two molecules linked by a disulfide bridge (GSSG).
• The enzyme glutathione reductase uses NADPH as a cofactor to reduce GSSG back to two moles of GSH.
• Glutathione maintains cysteine residues in hemoglobin and other proteins in a reduced state.
• People with G6PD deficiency must not eat Fava beans.
• RBCs with low levels of GSH are susceptible to hemolysis.
• G6PD deficiency is an inheritable X - linked recessive disorder.
• Mature RBCs have no mitochondria and are totally dependent on NADPH from the pentose phosphate pathway to regenerate GSH from GSSG via glutathione reductase.
• Approximately 10 - 14% of the male African American population is affected by G6PD deficiency.
• NADPH is a potent competitive inhibitor of the enzyme in the pentose pathway.
• Rapidly dividing cells require more ribose 5-phosphate than NADPH in the pentose pathway.
• Reduced glutathione (GSH) maintains the normal reduced state of the cell.
• Thiamine pyrophosphate (TPP) is a cofactor in the glycolytic pathway.
• Glucose 6-phosphate dehydrogenase (G6PD) is the regulatory enzyme in the pentose pathway.
• Mammary gland: as a mother’s body prepares to feed her offspring the enzymes of the PPP are switched on in the breast tissue.
• Muscle, by contrast, is not a biosynthetic tissue, and therefore has no need of the PPP enzymes.