The G6PD Pathway: Functions, Deficiency, and Importance

Glucose-6-Phosphate Dehydrogenase (G6PD) is an enzyme found in all human cells that is fundamental for cellular function. A deficiency in this enzyme is one of the most common human enzyme defects, affecting roughly 400 million people globally. The condition has a higher prevalence in individuals of African, Mediterranean, and Asian descent.

The G6PD Pathway: A Cellular Overview

The G6PD pathway, the initial step of the pentose phosphate pathway (PPP), is a metabolic process occurring in the cytoplasm of cells. Its purpose is to convert glucose-6-phosphate into other molecules the cell needs. The G6PD enzyme initiates and controls the speed of this entire pathway, making it the rate-limiting step.

This reaction produces two main products. The first is NADPH (nicotinamide adenine dinucleotide phosphate), a molecule that helps protect cells from damage. The second product is ribose-5-phosphate, a sugar that serves as a building block for the nucleotides that make up DNA and RNA.

Importance of NADPH and Red Blood Cell Protection

The NADPH produced by the G6PD pathway protects cells from oxidative stress. This type of stress is damage caused by an accumulation of reactive oxygen species, which are unstable byproducts of cellular processes. If not neutralized, these reactive molecules can harm cellular structures.

NADPH acts as a reducing agent, donating electrons to help regenerate the antioxidant glutathione, which directly neutralizes harmful reactive oxygen species. NADPH also supports catalase, another antioxidant enzyme that helps break down hydrogen peroxide.

This protective system is particularly important for red blood cells, which are at a high risk of oxidative damage due to their role in oxygen transport. Because red blood cells lack the internal structures for self-repair, the G6PD/NADPH pathway is their only defense against oxidative destruction.

Understanding G6PD Deficiency

G6PD deficiency is an inherited genetic condition where the body produces an insufficient amount of the G6PD enzyme or a version that does not function correctly. This defect results from mutations in the G6PD gene. A dysfunctional or insufficient enzyme means the G6PD pathway cannot operate effectively, leading to reduced NADPH production.

This reduction in NADPH impairs the ability of cells to defend against oxidative stress. Red blood cells are particularly vulnerable because they rely exclusively on this pathway. Without enough NADPH, they cannot regenerate the glutathione needed to neutralize damaging molecules, leaving them susceptible to premature destruction (hemolysis).

The condition is an X-linked recessive trait, as the G6PD gene is on the X chromosome. Because males have one X chromosome, a single mutated gene results in the deficiency. Females, having two X chromosomes, must inherit a mutated gene on both to have the full deficiency; more commonly, they are carriers with one mutated gene and experience no symptoms.

Triggers and Clinical Manifestations of G6PD Deficiency

Most individuals with G6PD deficiency do not experience daily issues. Problems arise upon exposure to factors that increase oxidative stress beyond what their red blood cells can handle. A well-known trigger is the consumption of fava beans or inhalation of their pollen, a reaction known as favism.

Other common triggers include:

• Certain antibiotics, such as sulfa drugs
• Medications used to treat malaria
• Aspirin
• Infections, which cause the body to generate high levels of oxidative molecules

When a person with G6PD deficiency encounters a trigger, their red blood cells break down rapidly. This leads to acute hemolytic anemia, where red blood cells are destroyed faster than the body can produce them. Symptoms can appear suddenly and include fatigue, paleness, shortness of breath, and a rapid heart rate.

The breakdown of red blood cells releases bilirubin, leading to jaundice (a yellowing of the skin and eyes) and dark, tea-colored urine. Neonatal jaundice appearing shortly after birth can also be an early sign of the deficiency.

Diagnosis and Living with G6PD Deficiency

G6PD deficiency is diagnosed through blood tests that measure the enzyme’s activity level in red blood cells. Other tests, like a complete blood count (CBC), can identify signs of hemolytic anemia. In regions where the condition is common, newborn screening programs are often used for early detection.

As there is no cure for this lifelong genetic condition, management focuses on prevention. The primary strategy is avoiding known oxidative triggers, including fava beans and specific medications. Most people with the deficiency live a normal life by being aware of and avoiding these triggers.

Genetic counseling can provide information about inheritance patterns for affected families. During a hemolytic crisis, supportive care is administered, which may include hydration or blood transfusions in severe cases.