Introduction to Pentose Phosphate Pathway to G6PD Deficiency: Biochemical Mechanism of Oxidative Stress

Content August 26, 2025

Pentose Phosphate Pathway: An Overview

Also called HMP shunt. Provides a source of NADPH from abundantly available glucose-6-P (NADPH is required for reductive reactions, eg, glutathione reduction inside RBCs, fatty acid and cholesterol biosynthesis). Additionally, this pathway yields ribose for nucleotide synthesis. Two distinct phases (oxidative and nonoxidative), both of which occur in the cytoplasm. No ATP is used or produced.

Sites of Pentose Phosphate Pathway Activity

The Pentose Phosphate Pathway is active in specific tissues: lactating mammary glands, liver, adrenal cortex (which are sites of fatty acid or steroid synthesis), and red blood cells (RBCs).

The pathway is divided into two main phases: an oxidative, irreversible phase, and a nonoxidative, reversible phase. Let’s look at the overall diagram.

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Oxidative Phase of the Pentose Phosphate Pathway

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The oxidative phase of the Pentose Phosphate Pathway is irreversible. It begins with Glucose-6-Phosphate, which is converted to 6-Phosphogluconolactone by the enzyme Glucose-6-Phosphate Dehydrogenase. This step is crucial as it produces the first molecule of NADPH from NADP+. Subsequently, 6-Phosphogluconolactone is converted to 6-Phosphogluconate, and then further to Ribulose-5-Phosphate, producing a second molecule of NADPH and releasing CO2. Ribulose-5-Phosphate is a key intermediate that can then enter the nonoxidative phase.

Nonoxidative Phase of the Pentose Phosphate Pathway

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The nonoxidative phase of the Pentose Phosphate Pathway is reversible and involves the interconversion of various sugars. Ribulose-5-Phosphate, produced in the oxidative phase, can be isomerized to Ribose-5-Phosphate, which is a precursor for nucleotide synthesis. Alternatively, Ribulose-5-Phosphate can be converted to Fructose-6-Phosphate and Glyceraldehyde-3-Phosphate through a series of reactions involving enzymes like Transketolase. These products, Fructose-6-Phosphate and Glyceraldehyde-3-Phosphate, can then re-enter glycolysis, linking the Pentose Phosphate Pathway to other metabolic routes.

G6PD Deficiency: NADPH’s Role and Hemolytic Anemia

NADPH is essential for maintaining reduced glutathione, which plays a vital role in detoxifying free radicals and peroxides. A deficiency in NADPH within red blood cells significantly impairs their defense against oxidizing agents, leading to hemolytic anemia. This vulnerability can be triggered by various substances, including fava beans, sulfonamides, nitrofurantoin, primaquine, chloroquine, and certain antituberculosis drugs. Infections are also a common cause, as the inflammatory response generates free radicals that diffuse into RBCs, causing oxidative damage and precipitating hemolysis.

G6PD Deficiency: Clinical Aspects and Diagnosis

Glucose-6-Phosphate Dehydrogenase deficiency is an X-linked recessive disorder and is the most common human enzyme deficiency globally. It is particularly prevalent among descendants of populations in malaria-endemic regions, such as sub-Saharan Africa and Southeast Asia. A hallmark of this condition is the formation of Heinz bodies, which are denatured globin chains that precipitate within red blood cells due to oxidative stress. The body attempts to remove these damaged cells, leading to the formation of “Bite cells,” which are red blood cells from which splenic macrophages have phagocytically removed the Heinz bodies. A helpful mnemonic is to “Bite into some Heinz ketchup.”

G6PD Deficiency: Biochemical Mechanism

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This diagram illustrates the critical role of Glucose-6-Phosphate Dehydrogenase, or G6PD, in protecting red blood cells from oxidative damage. G6PD converts Glucose-6-Phosphate to 6-Phosphogluconolactone, a reaction that produces NADPH from NADP+. NADPH is then used by Glutathione Reductase to reduce oxidized glutathione (GSSG) back to its reduced form (2 GSH). Reduced glutathione is essential for Glutathione Peroxidase, which detoxifies harmful hydrogen peroxide (H2O2) into water (2 H2O). In G6PD deficiency, the lack of NADPH impairs the reduction of glutathione, leading to an accumulation of reactive oxygen species and oxidative stress within the red blood cell.

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