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

TitleNADPH production by the oxidative pentose-phosphate pathway supports folate metabolism.
Publication TypeJournal Article
Year of Publication2019
AuthorsChen, L, Zhang, Z, Hoshino, A, Zheng, HD, Morley, M, Arany, Z, Rabinowitz, JD
JournalNat Metab
Volume1
Pagination404-415
Date Published2019 Mar
ISSN2522-5812
Abstract

NADPH donates high energy electrons for antioxidant defense 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 dihydrofolate reductase (DHFR), resulting in impaired folate-mediated biosynthesis, which is reversed by recombinant expression of E. 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.

Alternate JournalNat Metab
PubMed ID31058257
PubMed Central IDPMC6489125
Grant ListDP1 DK113643 / DK / NIDDK NIH HHS / United States
P30 CA072720 / CA / NCI NIH HHS / United States
P30 DK019525 / DK / NIDDK NIH HHS / United States
R01 CA163591 / CA / NCI NIH HHS / United States