Disease relevance of H6PD

• Glucose 6 phosphate dehydrogenase (G6PDH) deficiency is the most frequent cause of hemolytic anemias due to enzyme abnormality [1].
• This study demonstrates that a mild degree of G-6-PDH deficiency (comparable to the human class III G-6-PDH deficiencies) worsens erythrocyte dysfunction during sepsis [2].
• Evidence for functional convergence of redox regulation in G6PDH isoforms of cyanobacteria and higher plants [3].
• Increased erythrocyte rigidity and tendency for hemolysis together with alterations in band 3-spectrin interactions may contribute to the immunomodulatory effects of G-6-PDH deficiency observed after major trauma and infections in humans [2].
• It appeared that after 5 min of incubation at 37 degrees C the residual activity of G6PDH in an atmosphere of oxygen compared with nitrogen was 0% in normal liver tissue and 15% in normal colon epithelium, whereas in colon carcinoma and in colon carcinoma metastasis in liver it was 48% and 33%, respectively [4].

Psychiatry related information on H6PD

• Conclusions: Two population-based studies among Caucasian elderly showed no evidence for (combined) effects of two polymorphisms in the HSD11B1 and H6PD genes on body composition, adrenal androgen production, blood pressure, glucose metabolism, and incidence of dementia [5].
• Our results show that prolonged starvation leads to a pro-oxidant situation and oxidative stress despite activation of antioxidant defense mechanisms, and that inhibition of G6PDH activity might be responsible for this failure in cellular antioxidant defenses [6].

High impact information on H6PD

• The dissociation is reversible, and there are no permanent modifications of either G6PDH or its particulate binding site that affect binding [7].
• In unfertilized eggs of the sea urchin, Strongylocentrotus purpuratus, glucose-6-phosphate dehydrogenase (G6PDH) associates with the particulate elements remaining either after homogenization or extraction of eggs with non-ionic detergent in low ionic-strength media [7].
• In contrast, the variation of IFN-alphaR2c/G6PDH ratio at diagnosis was significantly associated with the achievement of major cytogenetic response (MCR; 34% or lower Ph(+) metaphases) [8].
• The enzyme, glucose-6-phosphate dehydrogenase (G6PDH, EC1.1.1.49), has long been considered and studied as the archetypical X-linked "housekeeping" enzyme that is present in all cells, where it plays the key role in regulating carbon flow through the pentose phosphate pathway [9].
• The molecular chaperone GroEL reverses the refolding kinetics of G6PDH from biphase back to monophase and accelerates the refolding process [10].

Chemical compound and disease context of H6PD

• We tested this hypothesis by demonstrating NAD-dependent lactate dehydrogenase (LDH) activity instead of NADP-dependent G6PDH activity in normal rat liver and colon, in human colon carcinoma, and in experimentally induced metastases of colon carcinoma in rat livers [4].
• Products of the reaction of 4-hydroxy-2-nonenal (4HNE) with native and heat-denatured Leuconostoc mesenteroides glucose-6-phosphate dehydrogenase (G6PDH) were analyzed to determine the structure and position of the protein modifications [11].
• We determined the activity of G-6-PDH as well as the penetration and metabolism of DHEA - diminished plasma concentrations of which have been found in psoriatics previously - in 16 patients with active psoriasis and 16 controls [12].
• It is possible that the intensification of G6PDH activity in carcinomas is a sign of the shift of the carbohydrate metabolism from an aerobic path or that the activity of the pentose shunt is higher because of the increased need for nucleic acid precursors in tissues with faster growth rates [13].
• NADPH is a powerful regulator of G6PDH activity in the normal astrocytes and in gliomas [14].

Biological context of H6PD

• CONCLUSIONS: Digenic triallelic genotypes of the H6PD R453Q variant and HSD11B1 83557insA mutation do not always cause CRD [15].
• On the contrary, the H6PD R453Q variant is associated with PCOS and might influence its phenotype by influencing adrenal activity [15].
• Results: No influence of the HSD11B1 83,557insA (allele frequencies 22.0 and 21.5%) and H6PD R453Q (allele frequencies 22.9 and 20.2%) variants was found for the different outcome measures that were investigated, either separately or when at least three alleles were affected [5].
• Novel SNPs were identified in both affected and unaffected individuals in GPR157 (c.795C>T [Arg218Leu]; c.811C>T [Ala223Val]), MGC4399 (c.1024G>C [Leu277Leu]), and H6PD (c.754A>C [Asp151Ala]) [16].
• Osmotic change, phosphate sequestration, or oxidative stress did not affect cytosolic G6PDH activity [17].

Anatomical context of H6PD

• In plants, Glc-6-phosphate dehydrogenase (G6PDH) isoenzymes are present in the cytosol and in plastids [17].
• This method was applied to determine zeptomoles of G6PDH in individual human erythrocytes [18].
• Post-embedment, EM immunogold labelling of G6PDH confirmed that this enzyme was localized in the peroxisomal matrices, the thylakoid membrane and matrix of chloroplasts, and the cytosol [19].
• Both enzymes, glucose-6-phosphate dehydrogenase (G6PDH; EC 1.1.1.49) and 6-phosphogluconate dehydrogenase (6PGDH; EC 1.1.1.44), were present in the matrix of leaf peroxisomes, and their kinetic properties were studied [19].
• Both dehydroepiandrosterone (DHEA) and the synthetic steroid 16 alpha-Br-epiandrosterone (Br-Epi), a more potent inhibitor of glucose-6-phosphate dehydrogenase (G6PDH) than DHEA, inhibit the 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulation of superoxide anion (O2-) formation by human neutrophils [20].

Associations of H6PD with chemical compounds

• Context: Recently, it was proposed that a combination of the 83,557insA polymorphism in the 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) gene and the R453Q polymorphism in the hexose-6-phosphate dehydrogenase (H6PD) gene interacts to cause cortisone reductase deficiency (CRD) when at least three alleles are affected [5].
• Using the published protein sequence from a rabbit microsomal glucose-6-phosphate dehydrogenase G6PD we have isolated and sequenced a cDNA clone coding for its human equivalent, which is also known as hexose-6-phosphate dehydrogenase (H6PD) and glucose dehydrogenase [21].
• In all species except the goby, two groups of isozymes were distinguished, corresponding to the mammalian G6PD (specific for glucose-6-phosphate (G6P) and NADP+) and H6PD (capable of utilizing galactose-6-phosphate and in certain cases other monosaccharide phosphates in addition to G6P) [22].
• The effects of polysaccharide, polyethylene glycol, and protein-crowding agents on the refolding of glucose-6-phosphate dehydrogenase (G6PDH) and protein disulfide isomerase have been examined [10].
• Obviously, in extended dark periods, G6PDH activity in the stroma is restricted but can be stimulated in response to high demands for NADPH [17].

Other interactions of H6PD

• Moreover, H6PD R453Q and HSD11B1 83557insA genotypes, either separately or in combination, did not influence 11betaHSD oxoreductase activity [15].
• CONTEXT: The R453Q variant in the hexose-6-phosphate dehydrogenase gene (H6PD) and 83557insA mutations in 11beta-hydroxysteroid dehydrogenase (11betaHSD) type 1 gene (HSD11B1) interact, resulting in cortisone reductase deficiency (CRD), a rare disorder characterized by a polycystic ovary syndrome (PCOS)-like phenotype [15].
• METHOD: The assay is based on the continuous measurement of released glucose by a coupled hexokinase/glucose-6-phosphate dehydrogenase (HK/G6PDH) reagent [23].
• The A. aeolicus G6PDH is a homodimer exhibiting remarkable thermostability (t1/2 = 24 hr at 90 degrees C) [24].
• Adaptational changes in kinetic parameters of G6PDH but not of PGDH during contamination-induced carcinogenesis in livers of North Sea flatfish [25].

Analytical, diagnostic and therapeutic context of H6PD

• By isoelectric focusing of peroxisomal matrices, the G6PDH activity was resolved into three isoforms with isoelectric points of 5.55, 5.30 and 4.85 [19].
• Sepsis (24 h) was induced by cecal ligation and puncture in wild-type (WT) and G-6-PDH-deficient (G-6-PDH activity 15% of WT) mice [2].
• A new commercially available homogeneous enzyme immunoassay, using the glucose-6-phosphate dehydrogenase (G6PDH) catalyzed conversion of NAD to NADH, has been evaluated and applied to the determination of acetaminophen in serum [26].
• RESULTS: Mass ratios of sucrose to raffinose did not affect the recovery of G6PDH activity after freeze-drying, but significantly affected the stability of freeze-dried G6PDH during storage [27].
• With increasing fraction of raffinose, the G6PDH stability decreased, sugar crystallization inhibited, and crystal-melting temperature increased [27].

References