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].
McDonagh Ellen M, Bautista José M, Youngster Ilan, Altman Russ B, Klein Teri E. "PharmGKB summary: methylene blue pathway" Pharmacogenetics and genomics (2013).
If you would like to reproduce this PharmGKB pathway diagram:
Entities in the Pathway
Relationships in the Pathway
|Arrow From||Arrow To||Controllers||PMID|
|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||G6PD||16204390, 18177777, 18226191, 20350285, 21376665|
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|PharmGKB summary: methylene blue pathway. Pharmacogenetics and genomics. 2013. McDonagh Ellen M, Bautista José M, Youngster Ilan, Altman Russ B, Klein Teri E.|
|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.|
|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.|
|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.|