Glucose-6-phosphate Dehydrogenase (G6PD) – Enzyme

What Is Glucose-6-phosphate Dehydrogenase?

Glucose-6-phosphate dehydrogenase (abbreviated G6PD) is an enzyme found in virtually all human cells. It plays a particularly critical role in red blood cells (erythrocytes), which lack nuclei and mitochondria and therefore rely entirely on the G6PD-dependent metabolic pathway to defend themselves against harmful oxidative damage.

G6PD catalyzes the first and rate-limiting step of the pentose phosphate pathway (also known as the hexose monophosphate shunt). In this reaction, glucose-6-phosphate is converted to 6-phosphogluconolactone, producing NADPH (nicotinamide adenine dinucleotide phosphate). NADPH is essential for regenerating glutathione, a key antioxidant that shields red blood cells from oxidative damage.

Function and Mechanism of Action

The primary function of G6PD is the production of NADPH, which serves several important roles:

• Reduction of oxidized glutathione (GSSG) back to its active form (GSH) via glutathione reductase
• Protection of red blood cells against reactive oxygen species (ROS) and other oxidative agents
• Participation in the biosynthesis of fatty acids, cholesterol, and nucleotides
• Support of immune defense through activation of phagocytes

Because red blood cells have no alternative route for NADPH production, they are especially vulnerable to oxidative stress when G6PD activity is reduced.

G6PD Deficiency: Causes and Inheritance

G6PD deficiency is the most common enzyme defect of red blood cells worldwide, affecting an estimated 400 to 500 million people globally. It is inherited in an X-linked recessive pattern, meaning the responsible gene is located on the X chromosome. Males (XY) are more frequently and more severely affected because they carry only one X chromosome, while females (XX) are often carriers and may exhibit milder symptoms.

The deficiency is most prevalent in regions historically affected by malaria, including sub-Saharan Africa, the Mediterranean, the Middle East, and Southeast Asia. This distribution reflects a phenomenon known as positive selection: G6PD deficiency appears to confer some protection against severe malaria.

Symptoms

Many individuals with G6PD deficiency remain asymptomatic as long as they avoid triggering factors. Symptoms typically manifest as hemolytic anemia -- the premature destruction of red blood cells. Common triggers include:

• Certain medications: e.g., primaquine, dapsone, nitrofurantoin, some sulfonamides, and high-dose aspirin
• Infections: bacterial or viral illnesses can induce oxidative stress
• Fava beans: contain oxidizing compounds; hemolysis triggered by fava bean consumption is called favism
• Chemical exposures: e.g., naphthalene (mothballs)

Typical symptoms of an acute hemolytic episode include:

• Yellowing of the skin and eyes (jaundice)
• Dark, brownish urine (due to released hemoglobin)
• Fatigue, weakness, and pallor
• Rapid heartbeat (tachycardia)
• Shortness of breath
• In severe cases: acute kidney injury

Newborns with G6PD deficiency may experience prolonged neonatal jaundice, which requires close medical monitoring and sometimes treatment.

Diagnosis

G6PD deficiency is diagnosed through several laboratory investigations:

• G6PD activity assay: direct measurement of enzyme activity in blood (gold standard)
• Fluorescent spot test: a rapid screening test that visualizes NADPH production
• Genetic testing: identification of mutations in the G6PD gene (over 200 variants are known)
• Complete blood count and reticulocyte count: to assess active hemolysis
• Haptoglobin, LDH, indirect bilirubin: standard hemolysis markers

Important note: During an acute hemolytic episode, G6PD activity may appear falsely normal because the most deficient cells have already been destroyed. Testing should ideally be performed at least 3 months after an acute episode to obtain reliable results.

Treatment and Management

There is currently no specific therapy to correct the enzyme deficiency. Management focuses on avoiding known triggers and treating acute episodes when they occur:

• Medication awareness: patients should inform all healthcare providers and pharmacists about their condition
• Avoiding fava beans: especially important for individuals with the Mediterranean G6PD variant
• Adequate hydration during infections
• Blood transfusions: in cases of severe hemolytic anemia
• Phototherapy or exchange transfusion: for severe neonatal jaundice
• Folic acid supplementation: to support red blood cell production in chronic hemolysis

With consistent avoidance of triggers, the overall prognosis is favorable. Severe chronic hemolytic anemia is rare and occurs only with certain uncommon G6PD variants.

References

1. WHO Working Group: Glucose-6-phosphate dehydrogenase deficiency. Bulletin of the World Health Organization, 67(6):601-611, 1989.
2. Luzzatto L, Nannelli C, Notaro R: Glucose-6-Phosphate Dehydrogenase Deficiency. Hematology/Oncology Clinics of North America, 30(2):373-393, 2016. PubMed PMID: 27040960.
3. Minucci A et al.: Glucose-6-phosphate dehydrogenase (G6PD) mutations database: Review of the old and update of the new mutations. Blood Cells, Molecules, and Diseases, 48(3):154-165, 2012.