What Does Glucose-6-Phosphate Dehydrogenase Do?

Glucose-6-phosphate dehydrogenase, usually called G6PD, is an enzyme found in virtually every cell in the human body. Its primary job is to produce a molecule called NADPH, which cells use to neutralize the dangerous byproducts of oxygen metabolism. Deficiency of this enzyme affects an estimated 400 million people worldwide, making it one of the most common inherited enzyme disorders in humans. The story of G6PD touches everything from ancient evolutionary pressures to modern malaria elimination campaigns, and understanding this single enzyme opens a window into how your cells defend themselves against chemical damage every second of the day.

What G6PD Does Inside Your Cells

G6PD sits at a metabolic crossroads. It catalyzes the first step of something called the pentose phosphate pathway, converting glucose-6-phosphate into another compound while simultaneously generating NADPH. That step is the bottleneck of the entire pathway, meaning G6PD controls how fast the whole process runs.¹ NADPH is the critical product here. Cells need it to power their antioxidant defenses, produce nitric oxide, run the cytochrome p450 system that metabolizes drugs, and fuel other essential processes.²

Think of NADPH as a rechargeable battery that powers your cell’s cleanup crew. Oxygen is necessary for life, but its byproducts are corrosive. Left unchecked, these reactive oxygen species damage proteins, fats in cell membranes, and DNA. Your cells depend on a constant supply of NADPH to keep antioxidant systems running and sweep these corrosive molecules away before they do harm. G6PD is the charger for that battery.

Why Red Blood Cells Bear the Brunt

G6PD deficiency causes problems throughout the body in severe cases, but red blood cells are disproportionately affected. The reason is simple: mature red blood cells have no nucleus and no mitochondria. Most other cells can generate NADPH through backup pathways, but red blood cells have essentially one source, and that source is G6PD. When the enzyme is missing or poorly functional, NADPH levels drop, and two major antioxidant systems in the red blood cell fail at once.

The first is the glutathione system. NADPH keeps glutathione in its active, reduced form, which scavenges harmful peroxides. The second is catalase, another enzyme that breaks down hydrogen peroxide and also depends on NADPH to stay active.³ Lose both of those systems simultaneously, and a red blood cell that could normally shrug off routine oxidative exposure becomes fragile. Membrane proteins begin to clump, the cell becomes rigid and misshapen, and the spleen flags it for destruction.⁴ When this happens on a large scale, you get hemolytic anemia: the body is destroying its own red blood cells faster than it can replace them.

Inheritance and the X Chromosome

The G6PD gene sits on the X chromosome, which makes its inheritance pattern different from most conditions people learn about in school. Males have one X chromosome and one Y, so a single defective copy of the G6PD gene means every red blood cell they produce carries the deficient enzyme. They are fully affected. Females have two X chromosomes, but early in development, one X chromosome in each cell is randomly switched off. A woman who carries one normal and one defective copy ends up with a mosaic: some of her red blood cells make normal G6PD and some make the deficient version.⁵

This mosaic pattern was actually one of the key pieces of evidence used to prove that X-chromosome inactivation happens randomly in women. Researchers studying women who carried two different forms of the G6PD enzyme (called type A and type B) found that individual cells expressed one or the other, never both, confirming that only one X chromosome was active per cell.⁶ The practical result for carrier women is highly variable symptoms. Some have enough normal red blood cells that they never have problems. Others, by chance, inactivated the normal X in most of their blood-forming cells and behave clinically much like deficient males.

What Triggers a Hemolytic Crisis

People with G6PD deficiency can go years without any symptoms. Trouble starts when something pushes oxidative stress beyond what their weakened defenses can handle. The triggers fall into three broad categories: certain foods, certain drugs, and infections.

The most famous food trigger is the fava bean. The connection is so well-established that the clinical term for it is “favism.” Fava beans contain compounds called vicine and convicine that generate powerful oxidants when metabolized. In surveys from Sardinia, where the severe Mediterranean variant of G6PD deficiency is common, raw beans caused hemolysis in over 90% of crisis cases in both children and adults.⁷ Cooking reduces the concentration of these compounds but does not eliminate the risk entirely in people with very low enzyme activity.

On the drug side, the original discovery of G6PD deficiency came from patients who developed severe anemia after taking the antimalarial drug primaquine. As far back as 1948, clinicians noticed that this class of drugs caused hemolysis in a predictable minority of patients.⁸ Today we understand that the metabolic byproducts of drugs like primaquine and dapsone generate oxidative stress that overwhelms the deficient red blood cell’s defenses. The drug metabolites cause a key structural protein in the red blood cell membrane, called band 3, to clump together and destabilize, leading to membrane breakdown.⁹

Infections are probably the most underappreciated trigger. Bacterial and viral infections activate the immune system’s oxidative burst, flooding tissues with reactive oxygen species as a weapon against pathogens. In someone with G6PD deficiency, this friendly fire can tip the balance and trigger red blood cell destruction. In severe G6PD variants, the enzyme deficit can even impair the immune cells themselves, weakening the oxidative burst that white blood cells use to kill bacteria.¹⁰

Newborn Jaundice and G6PD

One of the most clinically significant consequences of G6PD deficiency shows up within the first days of life. Newborns with deficient enzyme are at sharply increased risk for severe jaundice, and in the worst cases, the buildup of bilirubin can damage the brain permanently, a condition called kernicterus.¹¹ This risk exists even in countries with well-resourced healthcare systems.

The mechanism in neonatal jaundice is not identical to classic hemolytic crises in older children and adults. Rather than massive red blood cell destruction with visible membrane damage and Heinz body formation, the problem in newborns appears to involve impaired bilirubin clearance. The oxidant-antioxidant imbalance disrupts the recycling of a protein called peroxiredoxin 2, which interferes with the liver’s ability to process bilirubin efficiently.¹² This distinction matters because it means the jaundice can be severe even without obvious signs of hemolysis, making it easier to miss until bilirubin levels are dangerously high.

The Malaria Connection

G6PD deficiency is not distributed randomly around the world. It is concentrated in equatorial Africa, the Mediterranean, the Middle East, and Southeast Asia, regions with a long history of endemic malaria. This is not a coincidence. The deficiency appears to have been maintained in human populations by natural selection because it provides a survival advantage against malaria, at least for some carriers.

Research in sub-Saharan Africa has shown that in the most common African variant (called G6PD A−), the protective effect is concentrated in heterozygous females, those with a mosaic of deficient and normal red blood cells. In a study from Tanzania, heterozygous women were significantly protected against severe malaria. The proposed explanation is that the mosaic blood gives these women a partial defense against the parasite without the full vulnerability to hemolytic crises that comes with complete deficiency.¹³ The deficiency gene never spreads to fixation in the population because fully deficient individuals face risks from hemolysis and neonatal jaundice. The result is a classic evolutionary balancing act: the gene stays at a moderate frequency where the malaria protection it provides outweighs the harm it causes.

Severity Varies Enormously Between Variants

Not all G6PD deficiency is alike. More than 200 genetic variants of the G6PD gene have been identified, and they span a wide range of severity. A literature review of common variants found that residual enzyme activity in deficient males ranged from about 2% to 33% of normal, with extensive overlap between different variants.¹⁴

The World Health Organization historically grouped variants into classes based on residual enzyme activity. Class I variants were the most severe, causing chronic hemolytic anemia even without triggers. Class II had less than 10% residual activity, and Class III had 10% to 60%. In practice, however, researchers found that the enzyme activity levels of Class II and Class III variants overlapped so much that the distinction was not clinically useful. The WHO recently revised its classification, merging the old Class II and Class III into a single category called Class B, defined as having enzyme activity below 45% of normal.¹⁵

The most clinically important distinction remains between the common deficiency variants (now Class B) and the rare Class I variants that cause chronic non-spherocytic hemolytic anemia. Over 60 different mutations fall into this most severe category, and people with these variants have chronic, ongoing red blood cell destruction with intermittent worsening when exposed to oxidative stress, typically with enzyme activity below 10% of normal.¹⁶

Why the Enzyme’s Three-Dimensional Shape Matters

The active form of G6PD is not a single protein sitting alone. It functions as a pair (dimer) or a group of four (tetramer). Each individual unit has two domains: one binds the substrate glucose-6-phosphate, and the other binds the coenzyme NADP+. A separate “structural” NADP+ binding site, distinct from the catalytic one, plays a critical stabilizing role. It holds the dimer together.¹⁷

This architecture explains a puzzle about many disease-causing mutations: they are nowhere near the enzyme’s active site. Instead, the most severe (Class I) mutations cluster around the interface where the two halves of the dimer meet. Disrupting that interface destabilizes the whole enzyme, and an unstable enzyme is quickly degraded in the cell. Structural studies using crystallography and electron microscopy have shown that mutations at the noncatalytic NADP+ binding site ripple outward through a network of interactions, ultimately distorting the active site from a distance.¹⁸ Moderately severe variants, meanwhile, tend to cluster near the tetramer interface, and disrupting that interface drops enzyme activity below 10% of normal, confirming that the four-unit assembly is important for proper function.¹⁹

Testing for G6PD Deficiency

Accurate testing matters more than ever because new antimalarial drugs require knowing a patient’s G6PD status before prescribing. The gold standard is a laboratory spectrophotometric assay that measures enzyme activity quantitatively. But in malaria-endemic regions, laboratory infrastructure is often limited, so rapid diagnostic tests and point-of-care devices have become essential tools.

Qualitative rapid tests, which give a simple deficient-or-normal result, perform well for detecting severe deficiency. One widely used rapid test showed about 90% sensitivity for detecting severe deficiency and a negative predictive value above 98%, meaning it was excellent at confirming that someone could safely take primaquine.²⁰ The weakness of qualitative tests is that they tend to miss intermediate deficiency, which is common in heterozygous women. For those patients, quantitative point-of-care devices that measure actual enzyme activity levels are more informative. Field evaluations have found that newer quantitative devices achieve sensitivity and specificity above 90% when properly calibrated.²¹

G6PD Testing and Malaria Elimination

The practical urgency behind better testing comes from the global push to eliminate vivax malaria. Unlike other malaria species, Plasmodium vivax hides dormant forms in the liver that can reactivate months or years later. The only drugs that kill these dormant forms, primaquine and the newer tafenoquine, both cause hemolysis in G6PD-deficient patients. Without reliable G6PD testing, clinicians in endemic regions face an impossible choice: prescribe the drugs and risk a hemolytic crisis, or withhold them and guarantee the patient relapses.

Pilot programs in Brazil and Thailand have tested the feasibility of routine quantitative G6PD screening before prescribing radical cure. In a Thai program, all 316 vivax malaria patients were successfully screened with a point-of-care test, and appropriate drug selection based on G6PD status reached 100% for tafenoquine and daily primaquine. No confirmed drug-induced acute hemolytic anemia occurred in the study.²² Economic modeling from Brazil found that the tafenoquine-plus-screening approach was consistently cost-effective across multiple scenarios, with the greatest savings appearing when primaquine adherence was assumed to be low, since tafenoquine requires only a single dose rather than a multi-day course.²³

G6PD in Cancer and Metabolic Disease

The enzyme’s role extends well beyond red blood cells and malaria. Because rapidly dividing cells have enormous demand for the building blocks that the pentose phosphate pathway provides (particularly ribose sugars for DNA synthesis and NADPH for fat synthesis), G6PD is frequently ramped up in tumors. In liver cancer, G6PD messenger RNA levels are significantly elevated in tumor tissue compared to healthy tissue, and higher levels correlate with more advanced tumor grade, greater recurrence, and worse patient survival.²⁴ Similar overexpression has been documented in prostate cancer, where androgen signaling appears to drive G6PD upregulation to fuel cell growth.²⁵ Blocking G6PD in laboratory experiments inhibits tumor cell proliferation, which has led researchers to explore it as a potential drug target, though no G6PD inhibitors have reached clinical use for cancer treatment.²⁶

On the metabolic disease front, G6PD has been linked to chronic inflammation in obesity. In fat tissue, G6PD activity feeds NADPH into a pro-oxidant pathway rather than an antioxidant one, fueling the generation of reactive oxygen species in immune cells within fat deposits. This promotes the kind of chronic, low-grade inflammation that contributes to insulin resistance.²⁷ The same molecule that protects red blood cells from oxidative damage can, in a different cellular context, drive disease. It is a reminder that NADPH is not inherently “good” or “bad” but a versatile chemical currency whose effects depend entirely on which enzyme is spending it.

Treatment Options Today and on the Horizon

There are currently no approved drugs that correct G6PD deficiency itself. Management is almost entirely about avoidance: staying away from known trigger foods and medications, treating infections promptly, and monitoring newborns for jaundice. For acute hemolytic crises, treatment is supportive, with blood transfusions in severe cases and hydration to protect the kidneys from damage caused by the breakdown products of destroyed red blood cells.

Research is exploring several potential pharmacological strategies. One approach targets the glutathione pathway directly, trying to boost antioxidant capacity without relying on G6PD. Another investigates alternative cellular routes that can generate NADPH, essentially trying to reroute the cell’s metabolism around the bottleneck. A third line of research looks at drugs that might increase expression of the G6PD gene itself, coaxing cells into producing more of the enzyme from whatever functional gene copies exist.²⁸ Gene therapy remains a theoretical possibility, but the X-linked nature of the gene and the fact that red blood cells lack nuclei (meaning you would need to correct the gene in blood-forming stem cells) make it a challenging target. For now, the most impactful advances are happening not in treatment of the deficiency itself but in better screening tools that allow clinicians to safely prescribe medications that would otherwise be off-limits to deficient patients.

Neurodegenerative disease is another area where researchers are watching G6PD closely. The brain is metabolically voracious and highly susceptible to oxidative damage, and early work has begun mapping how reduced G6PD activity might contribute to neuronal vulnerability in conditions where oxidative stress plays a role.²⁹ This research is still in early stages, but it underscores how far-reaching the consequences of this single enzyme can be, well beyond the red blood cell problems that first brought it to medical attention.