Gene Number: 2539

Location: Xq28

Key Functions: Redox balance, antioxidant defense, NADPH generation, protection against oxidative stress, cellular detoxification

G6PD (glucose-6-phosphate dehydrogenase) encodes the rate-limiting enzyme of the pentose phosphate pathway (PPP), a crucial metabolic route parallel to glycolysis. Its principal role is to generate nicotinamide adenine dinucleotide phosphate (NADPH), the reducing power required to maintain the redox balance of cells and to preserve glutathione in its reduced form (GSH). This process is fundamental for protecting cellular components—especially lipids, proteins, and DNA—from oxidative damage induced by reactive oxygen species (ROS).

The pentose phosphate pathway operates predominantly in tissues with high demands for NADPH, such as the liver, adrenal glands, and red blood cells. In erythrocytes, where mitochondria are absent, G6PD serves as the sole source of NADPH. This makes its function indispensable for the regeneration of reduced glutathione, which neutralizes hydrogen peroxide and other oxidants. Without sufficient G6PD activity, red blood cells become highly vulnerable to oxidative stress, leading to membrane damage and premature cell destruction—a process known as hemolysis.

G6PD deficiency is the most common enzyme deficiency worldwide, affecting over 400 million individuals. It follows an X-linked inheritance pattern, meaning males are more likely to express clinical symptoms, while heterozygous females may show partial deficiency due to X-chromosome inactivation (lyonization). The disorder exhibits substantial genetic heterogeneity, with more than 200 known variants identified. These variants differ in their enzymatic stability and activity, leading to a spectrum of phenotypes ranging from asymptomatic carriers to severe hemolytic crises.

A defining characteristic of G6PD deficiency is oxidative sensitivity. Exposure to certain oxidative stressors—such as infections, sulfonamide antibiotics, antimalarials (e.g., primaquine), or ingestion of fava beans (favism)—can trigger acute hemolytic anemia. This results from the inability of deficient erythrocytes to neutralize oxidative compounds, causing rapid red blood cell breakdown, jaundice, and fatigue. In extreme cases, this can lead to neonatal jaundice or, rarely, hemoglobinuria and renal failure.

Interestingly, mild G6PD deficiency confers a degree of protection against severe malaria, particularly caused by Plasmodium falciparum. This selective advantage is thought to explain the high prevalence of G6PD variants in malaria-endemic regions—a classic example of balanced polymorphism in human evolution.

Beyond its hematologic role, NADPH generated by G6PD supports biosynthetic and detoxification pathways in other cell types. It fuels the regeneration of reduced thioredoxin and the activity of cytochrome P450 enzymes, enabling cholesterol synthesis, steroidogenesis, and xenobiotic detoxification. Moreover, in immune cells, G6PD-derived NADPH drives the respiratory burst, powering NADPH oxidase to generate ROS for pathogen destruction—a key component of the innate immune defense.

At the molecular level, G6PD gene expression is regulated by oxidative stress, hormones, and growth factors, ensuring that NADPH production adapts to metabolic demand. Mutations that destabilize the enzyme often affect residues critical for NADP+ binding or enzyme dimerization, reducing catalytic efficiency and making cells susceptible to oxidative damage.

In summary, G6PD functions as the cell’s redox gatekeeper, supplying the NADPH required for antioxidant defense, biosynthesis, and detoxification. Its deficiency illustrates the delicate balance between genetic adaptation and metabolic vulnerability—where evolutionary protection against malaria coincides with heightened oxidative sensitivity. Proper G6PD activity thus remains vital for maintaining red blood cell integrity, metabolic resilience, and overall oxidative homeostasis.