skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

This content will become publicly available on March 11, 2020

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

Abstract

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.

Authors:
ORCiD logo [1];  [1];  [2];  [1]; ORCiD logo [2];  [2]; ORCiD logo [1]
  1. Princeton Univ., Princeton, NJ (United States)
  2. Univ. of Pennsylvania, Philadelphia, PA (United States)
Publication Date:
Research Org.:
Center for Advanced Bioenergy and Bioproducts Innovation (CABBI), Urbana, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
OSTI Identifier:
1501460
Grant/Contract Number:  
SC0018420
Resource Type:
Accepted Manuscript
Journal Name:
Nature Metabolism
Additional Journal Information:
Journal Volume: 1; Journal Issue: 3; Journal ID: ISSN 2522-5812
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Chen, Li, Zhang, Zhaoyue, Hoshino, Atsushi, Zheng, Henry D., Morley, Michael, Arany, Zoltan, and Rabinowitz, Joshua D. NADPH production by the oxidative pentose-phosphate pathway supports folate metabolism. United States: N. p., 2019. Web. doi:10.1038/s42255-019-0043-x.
Chen, Li, Zhang, Zhaoyue, Hoshino, Atsushi, Zheng, Henry D., Morley, Michael, Arany, Zoltan, & Rabinowitz, Joshua D. NADPH production by the oxidative pentose-phosphate pathway supports folate metabolism. United States. doi:10.1038/s42255-019-0043-x.
Chen, Li, Zhang, Zhaoyue, Hoshino, Atsushi, Zheng, Henry D., Morley, Michael, Arany, Zoltan, and Rabinowitz, Joshua D. Mon . "NADPH production by the oxidative pentose-phosphate pathway supports folate metabolism". United States. doi:10.1038/s42255-019-0043-x.
@article{osti_1501460,
title = {NADPH production by the oxidative pentose-phosphate pathway supports folate metabolism},
author = {Chen, Li and Zhang, Zhaoyue and Hoshino, Atsushi and Zheng, Henry D. and Morley, Michael and Arany, Zoltan and Rabinowitz, Joshua D.},
abstractNote = {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.},
doi = {10.1038/s42255-019-0043-x},
journal = {Nature Metabolism},
number = 3,
volume = 1,
place = {United States},
year = {2019},
month = {3}
}

Journal Article:
Free Publicly Available Full Text
This content will become publicly available on March 11, 2020
Publisher's Version of Record

Save / Share: