NADPH production by the oxidative pentose-phosphate pathway supports folate metabolism

Chen, Li; Zhang, Zhaoyue; Hoshino, Atsushi; Zheng, Henry D.; Morley, Michael; Arany, Zoltan; Rabinowitz, Joshua D.

doi:10.1038/s42255-019-0043-x

Title: NADPH production by the oxidative pentose-phosphate pathway supports folate metabolism

Journal Article · Mon Mar 11 00:00:00 EDT 2019 · Nature Metabolism

DOI:https://doi.org/10.1038/s42255-019-0043-x· OSTI ID:1501460

^[1]; Zhang, Zhaoyue ^[1]; Hoshino, Atsushi ^[2]; Zheng, Henry D. ^[1];

^[2]; Arany, Zoltan ^[2];

^[1]

Princeton Univ., Princeton, NJ (United States)
Univ. of Pennsylvania, Philadelphia, PA (United States)

NADPH donates high-energy electrons for antioxidant defence and reductive biosynthesis. Cytosolic NADP is recycled to NADPH by the oxidative pentose-phosphate pathway (oxPPP), malic enzyme 1 (ME1) and isocitrate dehydrogenase 1 (IDH1). Here we show that any one of these routes can support cell growth, but the oxPPP is uniquely required to maintain a normal NADPH/NADP ratio, mammalian dihydrofolate reductase (DHFR) activity and folate metabolism. These findings are based on CRISPR deletions of glucose-6-phosphate dehydrogenase (G6PD, the committed oxPPP enzyme), ME1, IDH1 and combinations thereof in HCT116 colon cancer cells. Loss of G6PD results in high NADP, which induces compensatory increases in ME1 and IDH1 flux. But the high NADP inhibits DHFR, resulting in impaired folate-mediated biosynthesis, which is reversed by recombinant expression of Escherichia coli DHFR. Conclusively, across different cancer cell lines, G6PD deletion produced consistent changes in folate-related metabolites, suggesting a general requirement for the oxPPP to support folate metabolism.

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Research Organization:: Center for Advanced Bioenergy and Bioproducts Innovation (CABBI), Urbana, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: SC0018420

OSTI ID:: 1501460

Journal Information:: Nature Metabolism, Vol. 1, Issue 3; ISSN 2522-5812

Country of Publication:: United States

Language:: English

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