{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Glucose‐6‐phosphate dehydrogenase (G6PD) is the rate‐limiting enzyme of the pentose phosphate pathway, where it plays a central role in cellular metabolism by generating NADPH. NADPH is essential not only for reductive biosynthesis but also for maintaining redox homeostasis and supporting antioxidant defenses. G6PD variants can have significant clinical consequences. For instance, certain alleles (such as the G6PD G202A variant) decrease glycated hemoglobin levels, potentially leading to underdiagnosis of type 2 diabetes in populations where these variants are common."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, G6PD provides reducing power necessary for NADPH‐dependent reactions in diverse settings; one study demonstrated that in the endoplasmic reticulum, cytosolic G6PD collaborates with hexose-6-phosphate dehydrogenase to regenerate NADPH required for proper cortisone reduction."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Moreover, post-translational regulation of G6PD, such as deglutarylation mediated by SIRT5, enhances its activity and thereby reinforces a cell’s antioxidant capacity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In addition, activation of nuclear factor erythroid 2-related factor 2 (Nrf2)—which can be modulated by interactions with nuclear HO-1—results in upregulation of G6PD expression as part of a broader antioxidant response."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its role in maintaining redox balance, G6PD activity has important implications for human health. G6PD deficiency, one of the most common enzymopathies worldwide, is usually characterized by a reduction in enzyme stability and activity, leading to conditions such as neonatal jaundice and hemolytic anemia, particularly in response to oxidative stress."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In the context of infectious disease, the common African form of G6PD deficiency has been linked to a reduced risk of cerebral malaria while paradoxically increasing the risk of severe malarial anemia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Furthermore, studies in adipocytes indicate that an aberrant increase in G6PD expression stimulates adipogenesis and lipid accumulation, which in turn disrupts adipocytokine profiles and impairs insulin signaling, ultimately contributing to insulin resistance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Similarly, in conditions of acute organ injury such as renal ischemia-reperfusion, Nrf2-mediated induction of G6PD supports NADPH production that is crucial for counteracting oxidative damage."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings underscore the multifaceted roles of G6PD in regulating redox potential, biosynthetic processes, and metabolic homeostasis. Its central function in NADPH production links it to diverse physiological and pathophysiological processes—from protection against oxidative damage and modulation of inflammatory responses to influencing metabolic diseases and infection susceptibility.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Eleanor Wheeler, Aaron Leong, Ching-Ti Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Med (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pmed.1002383"}], "href": "https://doi.org/10.1371/journal.pmed.1002383"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28898252"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28898252"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Nicole Draper, Elizabeth A Walker, Iwona J Bujalska, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng1214"}], "href": "https://doi.org/10.1038/ng1214"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12858176"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12858176"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "A L Furfaro, N Traverso, C Domenicotti, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Nrf2/HO-1 Axis in Cancer Cell Growth and Chemoresistance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oxid Med Cell Longev (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1155/2016/1958174"}], "href": "https://doi.org/10.1155/2016/1958174"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26697129"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26697129"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Chhanda Biswas, Nidhi Shah, Manasa Muthu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nuclear heme oxygenase-1 (HO-1) modulates subcellular distribution and activation of Nrf2, impacting metabolic and anti-oxidant defenses."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M114.567685"}], "href": "https://doi.org/10.1074/jbc.M114.567685"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25107906"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25107906"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Philip J Mason, José M Bautista, Florinda Gilsanz "}, {"type": "b", "children": [{"type": "t", "text": "G6PD deficiency: the genotype-phenotype association."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood Rev (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.blre.2007.05.002"}], "href": "https://doi.org/10.1016/j.blre.2007.05.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17611006"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17611006"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Unknown Authors "}, {"type": "b", "children": [{"type": "t", "text": "Reappraisal of known malaria resistance loci in a large multicenter study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.3107"}], "href": "https://doi.org/10.1038/ng.3107"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25261933"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25261933"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Jiyoung Park, Ho Kyung Rho, Kang Ho Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Overexpression of glucose-6-phosphate dehydrogenase is associated with lipid dysregulation and insulin resistance in obesity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.25.12.5146-5157.2005"}], "href": "https://doi.org/10.1128/MCB.25.12.5146-5157.2005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15923630"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15923630"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Masahiro Nezu, Tomokazu Souma, Lei Yu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcription factor Nrf2 hyperactivation in early-phase renal ischemia-reperfusion injury prevents tubular damage progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Kidney Int (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.kint.2016.08.023"}], "href": "https://doi.org/10.1016/j.kint.2016.08.023"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27789056"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27789056"}]}]}]}