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Quantitative flux analysis reveals folate-dependent NADPH production
Jing Fan1, Jiangbin Ye2, Jurre J Kamphorst3
11] Department of Chemistry and Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08540, USA [2].
Nature
|May 9, 2014
Summary
Folate metabolism generates crucial reducing power for cells, alongside its role in synthesizing nucleic acids. This pathway is a significant source of cellular NADPH, essential for redox balance and cell survival.
Area of Science:
- Biochemistry
- Cell Biology
- Metabolic Pathways
Background:
- Adenosine triphosphate (ATP) is the primary energy currency for cellular work.
- Nicotinamide adenine dinucleotide phosphate (NADPH) is vital for redox defense and biosynthesis.
- While ATP production pathways are well-studied, NADPH metabolism requires further investigation.
Purpose of the Study:
- To quantify NADPH production fluxes from various metabolic pathways.
- To investigate the role of folate metabolism in cellular NADPH generation.
- To assess the impact of folate metabolism on cellular redox homeostasis.
Main Methods:
- Utilized liquid chromatography-mass spectrometry for tracking deuterium-labeled substrates into NADPH.
- Employed carbon labeling and mathematical modeling to measure metabolic fluxes.
- Performed gene knockdown of methylenetetrahydrofolate dehydrogenase (MTHFD) to assess functional significance.
Main Results:
- The oxidative pentose phosphate pathway is the largest contributor to cytosolic NADPH in proliferating cells.
- Serine-driven one-carbon metabolism significantly contributes to NADPH production.
- Mitochondrial one-carbon metabolism also generates NADPH through 10-formyl-tetrahydrofolate oxidation.
- MTHFD gene depletion reduced cellular NADPH levels and increased oxidative stress sensitivity.
Conclusions:
- Folate metabolism is a critical, previously unrecognized source of cellular NADPH.
- NADPH generated by folate metabolism is essential for maintaining redox balance (GSH/GSSG ratio).
- This pathway plays a dual role in proliferating cells: providing one-carbon units and generating reducing power.
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