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Glucose-6-Phosphate Dehydrogenase is a NADP+ dependent enzyme that catalyzes the conversion of Glucose-6-Phosphate to 6-Phosphoglucono-∂-Lactone, the committed step of Pentose phosphate pathway. The pentose phosphate pathway has great importance in the production of NADPH and pentose sugars. It is mainly found in the tissues where reductive biosynthesis occurs such as adipose tissue, RBCs, and mammary tissues. These tissues require the pentose phosphate pathway to produce plenty of NADPH for the reductive biosynthetic pathways. However, defective Glucose-6-Phosphate Dehydrogenase or its deficiency can lead to a serious problem where the pentose phosphate pathway is the main source of NADPH production.
NADPH is required for several reductive processes in addition to biosynthetic pathways. For example, erythrocytes require a lot of glutathione to reduce and eliminate hydrogen peroxide and organic hydroperoxides (these are reactive oxygen metabolites) that can irreversibly damage hemoglobin and cleave the C-C bonds in the phospholipid tail of the cell membranes. Accumulation of the peroxides results in the premature cell lysis. Therefore, peroxides are eliminated by Glutathione catalyzed by glutathione peroxidase.
Glutathione (GSH) is a cysteine-containing tripeptide the oxidized form of which is a Glutathione Disulfide (GSSG) with disulfide linkage. The oxidized form Glutathione Disulfide (GSSG) needs to be reduced back to Glutathione to continue the elimination of peroxides. Therefore, plenty of NADPH is required for the reduction of Glutathione Disulfide to Glutathione. This reduction is mediated by a NADPH-dependent enzyme; Glutathione Reductase.
Therefore, a constant supply of NADPH is vital for the erythrocytes to maintain the reducing environment. Erythrocytes in individuals with defective Glucose-6-Phosphate Dehydrogenase or its deficiency are sensitive to oxidative damage. As this enzyme is a committed step in the Pentose Phosphate Pathway, deficient enzyme production can lead to decreased or absence of production of NADPH in the erythrocytes thereby leading to several oxidative stresses.
Glucose-6-Phosphate Dehydrogenase deficiency is common in African, Asian and Mediterranean populations. It came to light through investigations of the hemolytic anemia induced in those individuals when they ingested drugs such as anti-malarial compounds or eat fava beans. These anti-malarial compounds stimulate peroxide formation thereby increasing the demand for NADPH to a level that cannot be met by mutant cells. However, fava beans contain toxic glycosides in a small amount that has the same effect i.e. formation of peroxide which requires ample of NADPH to be removed by Glutathione. This condition is called as favism.