Glucose-6-phosphate dehydrogenase (G6PD or G6PDH) (EC 1.1.1.49) is a cytosolic enzyme that catalyzes the chemical reaction This enzyme participates in the pentose phosphate pathway (see image), a metabolic pathway that supplies reducing energy to cells (such as erythrocytes) by maintaining the level of the reduced form of the co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH).

Clinically, an X-linked genetic deficiency of G6PD makes a human prone to non-immune hemolytic anemia.

[8] Some scientists have proposed that some of the genetic variation in human G6PD resulted from generations of adaptation to malarial infection.

In higher plants, several isoforms of G6PDH have been reported, which are localized in the cytosol, the plastidic stroma, and peroxisomes.

[4] The crystal structure of G6PD reveals an extensive network of electrostatic interactions and hydrogen bonding involving G6P, 3 water molecules, 3 lysines, 1 arginine, 2 histidines, 2 glutamic acids, and other polar amino acids.

Moreover, there is an extremely strong set of hydrophobic stacking interactions that result in overlapping π systems.

The structural site has been shown to be important for maintaining the long term stability of the enzyme.

[13] For example, two severe class I mutations, G488S and G488V, drastically increase the dissociation constant between NADP+ and the structural site by a factor of 7 to 13.

Mechanistically, acetylating Lys403 sterically hinders the NADP+ from entering the NADP+ structural site, which reduces the stability of the enzyme.

Cells sense extracellular oxidative stimuli to decrease G6PD acetylation in a SIRT2-dependent manner.

The SIRT2-mediated deacetylation and activation of G6PD stimulates pentose phosphate pathway to supply cytosolic NADPH to counteract oxidative damage and protect mouse erythrocytes.

Many variants of G6PD, mostly produced from missense mutations, have been described with wide-ranging levels of enzyme activity and associated clinical symptoms.

[19] Glucose-6-phosphate dehydrogenase deficiency is very common worldwide, and causes acute hemolytic anemia in the presence of simple infection, ingestion of fava beans, or reaction with certain medicines, antibiotics, antipyretics, and antimalarials.

[20] Pharmacologically ablating G6PD has been shown to overcome cross-tolerance of breast cancer cells to anthracyclines.