Pathway Pentose Phosphate Pathway (Erythrocyte)

A simplified diagram to show the role of G6PD in generating NADPH in red blood cells - this can then be utilized in the Oxidative Stress Regulatory and Methylene Blue Pathways.
Pentose Phosphate Pathway (Erythrocyte)
g6pd pgd hk1 gpi oxidative pathway Methylene pathway pgls
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The Pentose Phosphate Pathway (PPP) and production of NADPH in red blood cells

Glucose is converted to glucose-6-phosphate by hexokinase (HK1), and then enters either the glycolysis pathway via conversion to the isomer fructose-6-phosphate, or the PPP (also known as hexose monophosphate shunt) via oxidation into 6-phosphogluconolactone [Articles:18177777, 16204390, 21376665, 18226191, 17489100, 13799836, 15862084, 9531504]. Two steps within the PPP produce NADPH; the conversion of glucose-6-phosphate to 6-phosphogluconolactone by G6PD, and 6-phosphogluconate to ribulose-5-phosphate by 6-phosphogluconate dehydrogenase (PGD, 6PGD) [Articles:18177777, 16204390, 18226191, 21376665, 20350285]. The end product of the pathway is ribose-5-phosphate, utilized for the production of nucleotides, polysaccharides and coenzymes, and used in RBCs for phosphoribosylpyrophosphate (PRPP) production to generate ADP for use in the Embden-Meyerhof glycolysis pathway [Articles:21376665, 20122995, 7713590]. NADPH is required in the RBC for the regulation of oxidative stress and within the methylene blue pathway [Articles:21376665, 7489710, 7073040]. The only source of NADPH in RBCs is via the PPP, in which G6PD is the rate-limiting step [Articles:16204390, 2633878, 18177777, 4154443, 15862084, 21376665]. As RBCs age, enzyme activities involved in glucose metabolism diminish, including G6PD, reducing energy production and ability to protect cell membrane integrity and hemoglobin from oxidation [Articles:14074568, 13799836].

Authors: Ellen M. McDonagh, José M. Bautista, Ilan Youngster, Russ B. Altman, Teri E. Klein.
McDonagh Ellen M, Bautista José M, Youngster Ilan, Altman Russ B, Klein Teri E. "PharmGKB summary: methylene blue pathway" Pharmacogenetics and genomics (2013).
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Therapeutic Categories:
  • Physiological mechanisms

Entities in the Pathway

Genes (5)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
6-phosphogluconate Ribulose-5-phosphate PGD 18177777, 18226191
6-phosphogluconolactone 6-phosphogluconate PGLS 10518023, 11457850
Fructose-6-phosphate Glucose-6-phosphate 18226191, 21376665
Glucose Glucose-6-phosphate HK1 13799836, 16204390, 18177777, 21376665
Glucose-6-phosphate 6-phosphogluconolactone G6PD 16204390, 18177777, 18226191, 20350285, 21376665
Glucose-6-phosphate Fructose-6-phosphate GPI 13799836, 18226191, 21376665
NADP NADPH PGD 18177777, 18226191
NADP NADPH G6PD 16204390, 18177777, 18226191, 20350285, 21376665
Ribulose-5-phosphate Ribose-5-phosphate
Glucose transporters 15862084
transporters Glucose

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Related Publications

PharmGKB summary: methylene blue pathway. Pharmacogenetics and genomics. 2013. McDonagh Ellen M, Bautista José M, Youngster Ilan, Altman Russ B, Klein Teri E. PubMed
Haemolysis risk in methylene blue treatment of G6PD-sufficient and G6PD-deficient West-African children with uncomplicated falciparum malaria: a synopsis of four RCTs. Pharmacoepidemiology and drug safety. 2012. Müller Olaf, Mockenhaupt Frank P, Marks Bernd, Meissner Peter, Coulibaly Boubacar, Kuhnert Ronny, Buchner Hannes, Schirmer R Heiner, Walter-Sack Ingeborg, Sié Ali, Mansmann Ulrich. PubMed
Aspirin-induced acute haemolytic anaemia in glucose-6-phosphate dehydrogenase-deficient children with systemic arthritis. Acta haematologica. 1989. Meloni T, Forteleoni G, Ogana A, Franca V. PubMed
Failure of methylene blue treatment in toxic methemoglobinemia. Association with glucose-6-phosphate dehydrogenase deficiency. Annals of internal medicine. 1971. Rosen P J, Johnson C, McGehee W G, Beutler E. PubMed