Quantitative flux analysis reveals folate-dependent NADPH production
Open accessAbstract
ATP is the dominant energy source in animals for mechanical and electrical work (for example, muscle contraction or neuronal firing). For chemical work, there is an equally important role for NADPH, which powers redox defence and reductive biosynthesis. The most direct route to produce NADPH from glucose is the oxidative pentose phosphate pathway, with malic enzyme sometimes also important. Although the relative contribution of glycolysis and oxidative phosphorylation to ATP production has been extensively analysed, similar analysis of NADPH metabolism has been lacking. Here we demonstrate the ability to directly track, by liquid chromatography-mass spectrometry, the passage of deuterium from labelled substrates into NADPH, and combine this approach with carbon labelling and mathematical modelling to measure NADPH fluxes. In proliferating cells, the largest contributor to cytosolic NADPH is the oxidative pentose phosphate pathway. Surprisingly, a nearly comparable contribution comes from serine-driven one-carbon metabolism, in which oxidation of methylene tetrahydrofolate to 10-formyl-tetrahydrofolate is coupled to reduction of NADP(+) to NADPH. Moreover, tracing of mitochondrial one-carbon metabolism revealed complete oxidation of 10-formyl-tetrahydrofolate to make NADPH. As folate metabolism has not previously been considered an NADPH producer, confirmation of its functional significance was undertaken through knockdown of methylenetetrahydrofolate dehydrogenase (MTHFD) genes. Depletion of either the cytosolic or mitochondrial MTHFD isozyme resulted in decreased cellular NADPH/NADP(+) and reduced/oxidized glutathione ratios (GSH/GSSG) and increased cell sensitivity to oxidative stress. Thus, although the importance of folate metabolism for proliferating cells has been long recognized and attributed to its function of producing one-carbon units for nucleic acid synthesis, another crucial function of this pathway is generating reducing power.
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Serine can contribute to NADPH production via the folate cycle, which maintains redox homeostasis and supports anabolic reactions.
“Serine can also contribute to NADPH production via the folate cycle, which serves to maintain redox homeostasis and support anabolic reactions (Fan et al., 2014; Lewis et al., 2014; Ye et al., 2014).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Fan et al., 2014
Stepwise oxidation of one-carbon-THF species produces up to 50% of all cellular NADPH.
“stepwise oxidation of one-carbon-THF species was recently shown to produce up to 50% of all cellular NADPH”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Fan et al., 2014
MTHFD2 plays a role in redox homeostasis through its cofactor NAD+ and through involvement with expression of hypoxia-related proteins such as HIF-2α.
“In addition to its involvement in nutrient regulation, MTHFD2 plays a role in redox homeostasis through the use of its cofactor NAD+, as well as involvement with expression of hypoxia-related proteins such as HIF-2α.”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [192]
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- Authors
- Fan, J., Ye, J., Kamphorst, J. J., Shlomi, T., Thompson, C. B., & Rabinowitz, J. D.
- Affiliations
- Princeton University (US)
- Memorial Sloan Kettering Cancer Center (US)
- Technion – Israel Institute of Technology (IL)
- Corresponding author
- Rabinowitz, Joshua D.
- Venue
- Nature
- Published
- 2014-05-04
- Volume
- 510
- Issue
- 7504
- Pages
- 298-302
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4104482
- OpenAlex
- W2017035524
- Cited by
- 1,114
- References
- 41
- Citations by year
- 2026: 65 · 2025: 90 · 2024: 91 · 2023: 79 · 2022: 87 · 2021: 116 · 2020: 109 · 2019: 102 · 2018: 65 · 2017: 106 · 2016: 98 · 2015: 74 · 2014: 31
- FWCI
- 86.15
- Type
- journal article
- Language
- en
- Update notices
- erratum (2014-09-24)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Memorial Sloan-Kettering Cancer Center
- National Institutes of Health
- National Cancer Institute (P01CA104838, R01CA105463, P30CA072720, R01CA163591)
- National Institute of General Medical Sciences (P50GM071508)
- National Institute of Allergy and Infectious Diseases (R01AI097382)
- Topics
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- NADPH production, folate metabolism, methylenetetrahydrofolate dehydrogenase, oxidative pentose phosphate pathway, one-carbon metabolism, serine metabolism, glycine metabolism, deuterium labeling, carbon labeling
- MeSH terms
- Animals, Carbon, Cell Line, Leucovorin, Cytosol, Folic Acid, Glutathione, Glycine, Humans, Isoenzymes, Methylenetetrahydrofolate Dehydrogenase (NADP), Mitochondria, NADP, Oxidation-Reduction, Pentose Phosphate Pathway, Serine, Tetrahydrofolates, Oxidative Stress, Cell Line, Tumor, Mice, HEK293 Cells
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