Pentose Phosphate Pathway

• The oxidative environment induced by G6PD deficiency might hinder the parasite's ability to handle oxidative stress, affecting its growth.
• Pentose phosphate pathway, also known as Hexose Monophosphate Shunt, Phosphogluconate pathway, occurs in the cytosol and is a shunt that begins with the glycolytic intermediate glucose 6-P.
• The pathway 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.
• The pathway yields ribose 5-phosphate, which is used in nucleotide biosynthesis leading to DNA, RNA, and various cofactors (CoA, FAD, SAM, NAD+/NADP+).
• NADPH is a phosphorylated form of NADH, which is used to drive the phosphorylation of ADP to ATP.
• NADPH is used where reducing potential is required for synthetic reactions.
• The Pentose Phosphate Pathway can be divided into two phases: the Oxidative Pathway and the Non-Oxidative Pathway.
• NADPH + H+ production occurs through two distinct reactions: the reaction catalyzed by glucose 6-phosphate dehydrogenase (G6PD) serves as the rate-limiting step and is almost entirely irreversible.
• Cells prioritize the generation of NADPH over ribose 5-phosphate due to the higher demand for NADPH compared to ribose 5-phosphate in cellular processes.
• The enzyme transketolase (TPP) requires the coenzyme thiamine pyrophosphate (TPP), while the enzyme transaldolase does not.
• Ingested ribose can enter the glycolytic pathway through the pentose pathway.
• G6PD plays a pivotal role in controlling the rate of the pentose phosphate pathway.
• The activity of G6PD determines the production of NADPH, which is crucial for various cellular processes.
• GSH serves as a potent antioxidant by directly neutralizing peroxides through a reaction catalyzed by the enzyme glutathione peroxidase:
• Reduced glutathione (GSH) plays a crucial role in detoxifying peroxides, such as hydrogen peroxide (H2O2), which can cause oxidative damage within cells.
• When red blood cells (RBCs) have low levels of reduced glutathione (GSH), they become more susceptible to oxidative damage and are prone to hemolysis, which is the premature destruction or rupture of RBCs.
• In certain cases, this hemolysis can result in the appearance of dark-colored urine, known as hemoglobinuria or, more specifically, black urine, which can occur under certain conditions of severe hemolysis.
• Fava beans contain a purine glycoside called vicine or divicine, which in G6PD-deficient individuals, can generate oxidative stress, triggering hemolytic anemia.
• Clinically, this condition can manifest as hemolytic anemia, characterized by a decreased number of RBCs due to their premature destruction.
• Certain substances act as oxidative agents, generating peroxides or ROS that can overwhelm the antioxidant capacity of RBCs lacking sufficient GSH due to G6PD deficiency.
• This discoloration is due to the presence of hemoglobin breakdown products in the urine.
• Primaquine, an antimalarial drug, can induce oxidative stress in G6PD-deficient individuals, leading to hemolysis upon exposure.
• As a result, the RBCs become fragile and prone to rupture, leading to hemolysis.
• In individuals with reduced levels of GSH, there's an increased risk of hemolysis.
• Reduced levels of GSH compromise the RBCs' ability to neutralize peroxides, leading to increased oxidative stress within the cells.
• Several conditions or triggers can induce hemolytic crises in individuals with G6PD deficiency.
• When the ratio of NADPH to NADP+ is high, it signals that the cell has sufficient NADPH.
• This high ratio tends to inhibit the activity of G6PD as a part of a negative feedback mechanism.
• When there's an increased demand for NADPH, the NADPH/NADP+ ratio decreases, signaling the need for more NADPH production.
• As a result, the inhibition on G6PD is relieved, and the enzyme's activity is stimulated to produce more NADPH to meet the cellular demands.
• Rapidly dividing cells require more ribose 5-phosphate than NADPH.
• The need for NADPH and ribose 5-phosphate is balanced during fatty acid synthesis in adipose cells, where NADPH is essential for the reduction reactions that convert acetyl-CoA into fatty acids.
• These reduction reactions require NADPH as a reducing agent to add hydrogen atoms and form the fatty acid molecules.
• In this context, while ribose 5-phosphate is also a product of the pentose phosphate pathway and serves as a precursor for nucleotide synthesis, the demand for NADPH is relatively higher during fatty acid synthesis.
• Glutathione is involved in the transport of amino acids across cell membranes, playing a role in maintaining the redox state and regulating the transport of certain amino acids, contributing to cellular homeostasis and protein synthesis.
• In RBCs, the PPP plays a crucial role in providing NADPH, which is utilized primarily by glutathione reductase to maintain the pool of reduced glutathione (GSH).
• Glutathione's ability to scavenge ROS helps prevent oxidative damage to these crucial cellular components, preserving their structural integrity and functionality.
• When GSH neutralizes ROS, it becomes oxidized in the process, forming the oxidized form of glutathione, known as glutathione disulfide (GSSG).
• Glutathione helps to counteract oxidative stress by donating electrons to neutralize reactive oxygen species (ROS) and free radicals, thereby protecting cells from oxidative damage.