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

Nature Metabolism
Li ChenJoshua D Rabinowitz

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. 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.

References

Jan 8, 2000·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·C J NicolP G Wells
Jul 16, 2004·The Journal of Biological Chemistry·Ho-Jin KohTae-Lin Huh
Jan 8, 2008·Lancet·M D Cappellini, G Fiorelli
Aug 30, 2008·Nature Chemical Biology·Yun Kyung KwonJoshua D Rabinowitz
Jul 23, 2009·Journal of Biotechnology·Christian M MetalloGregory Stephanopoulos
Jul 22, 2010·Annual Review of Nutrition·Anne S Tibbetts, Dean R Appling
Nov 6, 2010·Analytical Chemistry·Eugene MelamudJoshua D Rabinowitz
Oct 12, 2011·Annual Review of Cell and Developmental Biology·Sophia Y Lunt, Matthew G Vander Heiden
Nov 22, 2011·Nature·Christian M MetalloGregory Stephanopoulos
Nov 23, 2011·Proceedings of the National Academy of Sciences of the United States of America·David R WiseCraig B Thompson
Jun 5, 2013·Proceedings of the National Academy of Sciences of the United States of America·C Tony LiuStephen J Benkovic
Jul 5, 2013·Nature Reviews. Cancer·Jason W Locasale
Oct 26, 2013·Nature Protocols·F Ann RanFeng Zhang
Nov 16, 2013·Malaria Journal·Rosalind E HowesSimon I Hay
May 9, 2014·Nature·Jing FanJoshua D Rabinowitz
Jun 3, 2014·Molecular Cell·Caroline A LewisChristian M Metallo
Jul 31, 2014·Nature Methods·Neville E SanjanaFeng Zhang
Sep 5, 2014·Cancer Discovery·Jiangbin YeCraig B Thompson
Dec 31, 2014·Proceedings of the National Academy of Sciences of the United States of America·Martha S FieldPatrick J Stover
Mar 4, 2015·Current Opinion in Biotechnology·Joerg M BuescherSarah-Maria Fendt
Oct 16, 2015·Nature·Elena PiskounovaSean J Morrison
Mar 22, 2016·Nature Chemical Biology·Ling LiuJoshua D Rabinowitz
May 24, 2016·Cell Metabolism·Gregory S DuckerJoshua D Rabinowitz
Sep 17, 2016·Nature Reviews. Cancer·Ming Yang, Karen H Vousden
Sep 20, 2016·Cell Metabolism·Gregory S Ducker, Joshua D Rabinowitz
May 5, 2017·Analytical Chemistry·Xiaoyang SuJoshua D Rabinowitz
Sep 16, 2017·Journal of the American Chemical Society·Zhaoyue ZhangJoshua D Rabinowitz
Oct 19, 2017·Nature·Sheng HuiJoshua D Rabinowitz

❮ Previous
Next ❯

Citations

Jul 11, 2020·ELife·Allison N LauMatthew G Vander Heiden
May 13, 2020·Nature Chemical Biology·Jonathan M GhergurovichJoshua D Rabinowitz
Jun 24, 2020·Nature Chemical Biology·Michael E Pacold
Jul 8, 2020·Antioxidants & Redox Signaling·Jingwen JiangCanhua Huang
Nov 7, 2019·Nature Reviews. Cancer·Gerta Hoxhaj, Brendan D Manning
Mar 5, 2020·Archives of Pharmacal Research·Eun-Ji Choi, Sang-Min Jeon
Sep 10, 2020·Cells·Mohaned BenzartiJohannes Meiser
Sep 16, 2020·Cells·Eunae Sandra ChoJong In Yook
Sep 11, 2019·Cells·Hung-Chi YangDaniel Tsun-Yee Chiu
Dec 5, 2019·Frontiers in Microbiology·Adhish S Walvekar, Sunil Laxman
Jul 9, 2020·Apoptosis : an International Journal on Programmed Cell Death·Mehrdad GhashghaeiniaMartin Köberle
Nov 7, 2019·The Journal of Cell Biology·Miguel Reina-CamposJorge Moscat
Oct 14, 2020·Nature Metabolism·Ruben BoonRaul Mostoslavsky
Oct 9, 2020·Signal Transduction and Targeted Therapy·Huai-Qiang JuRui-Hua Xu
Oct 22, 2020·Cancers·Janine M DeBlasi, Gina M DeNicola
May 22, 2019·Molecular Cancer Research : MCR·Erika S DahlKatherine M Aird
Jul 15, 2020·Cancer Research·Jonathan M GhergurovichJoshua D Rabinowitz
Nov 7, 2020·Frontiers in Bioengineering and Biotechnology·Eugene Fletcher, Kristin Baetz
Feb 13, 2021·Metabolites·Joohwan Kim, Gina Lee
Oct 30, 2020·Frontiers in Cell and Developmental Biology·Guo LiWei-Guo Zhu
Mar 5, 2021·Pharmacology & Therapeutics·Lingfan LiangZeping Hu
Mar 13, 2021·Leukemia·Martha M ZarouG Vignir Helgason
Jun 3, 2021·Nutrients·Michael F ColemanStephen D Hursting
Jun 3, 2021·Biomolecules·Liang-Jun Yan
May 20, 2021·Oxidative Medicine and Cellular Longevity·Maria Pina DoreGiovanni Mario Pes
Jun 5, 2021·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Abir MondalSoumya Pati
Jul 2, 2021·Laboratory Investigation; a Journal of Technical Methods and Pathology·Yujue WangXiaoyang Su
Jul 21, 2021·Trends in Plant Science·Edward N SmithNicholas J Kruger
Aug 15, 2021·Trends in Pharmacological Sciences·Adriana A GarciaDaria Mochly-Rosen
Aug 28, 2021·International Journal of Molecular Sciences·Sonia E TrojanKinga A Kocemba-Pilarczyk

❮ Previous
Next ❯

Methods Mentioned

BETA
targeted knockout
gene knockout
gene knockouts
gel filtration
protein assay

Software Mentioned

ElMaven
Q Exactive Plus
Cluster
MAVEN
GraphPad Prism
Treeview

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.