NADPH deficiency

The pentose phosphate pathway is the only source of NADPH in red blood cells, which, as a result, are highly dependent on the proper functioning of the enzymes involved. A glucose-6-phosphate dehydrogenase deficiency leads to an NADPH deficiency, which can, in turn, lead to hemolytic anemia because of wholesale destruction of red blood cells. 

The relationship between NADPH deficiency and anemia is an indirect one. NADPH is required to reduce the peptide glutathione from the disulfide to the free thiol form. Mammalian red blood cells lack mitochondria, which host many redox reactions. 

An en2ymatic method for assessing riboflavin deficiency in humans has been developed (74). It is based on the fact that NADPH-dependent glutathione reductase of red cells reflects riboflavin fluctuations. 

NADPH quinone oxido-reductase 1 Pro187Ser variant occurring with about 5% frequency is functionally almost completely deficient. Impaired activity associated with benzene toxicity and cancer chemotherapy induced leukemia. 

Genetic deficiency of glucose-6-phosphate dehydrogenase, with consequent impairment of the generation of NADPH, is common in populations of Mediterranean and Afro-Caribbean origin. The defect is manifested as red cell hemolysis (hemolytic anemia) when susceptible individuals are subjected to oxidants, such as the an-timalarial primaquine, aspirin, or sulfonamides or when... 

The pentose phosphate pathway is operative in the RBC (it metabolizes about 5-10% of the total flux of glucose) and produces NADPH hemolytic anemia due to a deficiency of the activity of glucose-6-phosphate dehydrogenase is common. 

NADPH-oxidase j 2O2 + NADPH 20p + NADP -F H+ Key component of the respiratory burst Deficient in chronic granulomatous disease... 

NADPH oxidase deficiency and catalase positive organisms in chronic granulomatous disease... 

Additionally, the myeloperoxidase system even regulates the duration of the respiratory burst because neutrophils from patients with myeloperoxidase deficiency (see 8.3) generate more reactive oxidants than control cells. Also, when myeloperoxidase is inhibited with a specific antibody or a specific inhibitor such as salicylhydroxamic acid, the duration of the respiratory burst, but not the maximal rate of oxidant production, is extended. This indicates that a product of the myeloperoxidase system inhibits the NADPH oxidase and so self-regulates reactive oxidant production during inflammation. 

The second major breakthrough in understanding the defect in CGD neutrophils came through the development of assays in which the NADPH oxidase can be activated in a cell-free system in vitro ( 5.3.2.3). In these systems, activation of the oxidase can be achieved by the addition of cytoplasm to plasma membranes in the presence of NADPH and arachidonic acid (or SDS or related substances). Interestingly, the oxidase cannot be activated in these cell-free systems using extracts from CGD neutrophils however, cytosol and plasma membranes from normal and CGD neutrophils may be mixed, and in most cases activity is restored if the correct mixing pattern is used. For example, as may be predicted, in X-linked CGD it is the membranes that are defective (because the cytochrome b is deficient), whereas in autosomal recessive CGD the cytosol is defective in the cell-free system. 

Pentose phosphate pathway (= hexose monophosphate shunt) generation of NADPH G6PDH deficiency... 

Chronic granulomatous disease is most frequently aused by genetic deficiency of NADPH oxidase in the PMN. Patients are susceptible to infection by catalasepositive organisms such as Staphylococcus aureus, Klebsiella, Escherichia coll, Candida, end Aspergillus, k negative nitroblue tetrazolium test is useful in confirming the diagnosis. 

Persons with G6PD deficiency are normally asymptomatic, but their RBCs are susceptible to oxidative damage because they have impaired production of NADPH. 

RBCs are especially sensitive to G6PD deficiency because the PPP is the only source of NADPH in these cells. 

While defective 11/1HSD I seemed the most likely cause of the disorder, no loss-of-function mutations were found in 1 IjSHSD I in the first patients investigated [61 ]. The cause of the disorder in these cases proved to be mutations in hexose-6-phos-phate dehydrogenase (H6PDH), the enzyme that supplies electrons to the NADPH utilized in oxidoreduction [15]. Later studies have found 11/311814 I mutations in some affected individuals. Thus, there are two monogenic disorders giving rise to a similar phenotype cortisone reductase deficiency caused by lljSHSD I mutations,... 

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