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. 2021 Oct 14;11(11):2682–2692. doi: 10.1158/2159-8290.CD-21-0558

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©2021 The Authors; Published by the American Association for Cancer Research

This open access article is distributed under the Creative Commons Attribution License 4.0 International (CC BY).

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Figure 1. Metabolic pathways that generate NADPH are important sources of reducing equivalents for oxidative stress resistance. A, Glutathione (GSH) and thioredoxin (TRXred) are redox buffers that are used by antioxidant enzymes such as superoxide dismutase (SOD), peroxiredoxin (PRDX), and glutathione peroxidase 4 (GPX4) to neutralize ROS, including O2−, H2O2, and lipid ROS. The reduced forms of GSH and TRX can then be regenerated from the oxidized forms [glutathione disulfide (GSSG); TRXox] by glutathione reductase (GR) or thioredoxin reductase (TRXR), which obtain reducing equivalents from NADPH. NADP+ is generated de novo from NAD+ by NAD kinase (NADK; ref. 167). NADP+ is then reduced to NADPH by the pentose phosphate pathway, the folate pathway, malic enzyme (ME1, 2, or 3), glutamate dehydrogenase (GDH1/2), or isocitrate dehydrogenase (IDH1/2; ref. 86). Other abbreviations in this panel include electron transport chain (ETC), glucose-6-phosphate dehydrogenase (G6PD), phosphogluconate dehydrogenase (PGD), dihydrofolate reductase (DHFR), methylenetetrahydrofolate dehydrogenase 1/2 (MTHFD1/2), NADPH oxidase (NOX), superoxide dismutase (SOD), and catalase (CAT). B, Schematic of reactions in which antioxidant enzymes transfer reducing equivalents between NADPH, GSH, and ROS. — Metabolic pathways that generate NADPH are important sources of reducing equivalents for oxidative stress resistance. A, Glutathione (GSH) and thioredoxin (TRX_red) are redox buffers that are used by antioxidant enzymes such as superoxide dismutase (SOD), peroxiredoxin (PRDX), and glutathione peroxidase 4 (GPX4) to neutralize ROS, including O₂⁻, H₂O₂, and lipid ROS. The reduced forms of GSH and TRX can then be regenerated from the oxidized forms [glutathione disulfide (GSSG); TRX_ox] by glutathione reductase (GR) or thioredoxin reductase (TRXR), which obtain reducing equivalents from NADPH. NADP⁺ is generated de novo from NAD⁺ by NAD kinase (NADK; ref. 167). NADP⁺ is then reduced to NADPH by the pentose phosphate pathway, the folate pathway, malic enzyme (ME1, 2, or 3), glutamate dehydrogenase (GDH1/2), or isocitrate dehydrogenase (IDH1/2; ref. 86). Other abbreviations in this panel include electron transport chain (ETC), glucose-6-phosphate dehydrogenase (G6PD), phosphogluconate dehydrogenase (PGD), dihydrofolate reductase (DHFR), methylenetetrahydrofolate dehydrogenase 1/2 (MTHFD1/2), NADPH oxidase (NOX), superoxide dismutase (SOD), and catalase (CAT). B, Schematic of reactions in which antioxidant enzymes transfer reducing equivalents between NADPH, GSH, and ROS.