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Mol Cell. 2019 Dec 19;76(6):857-871.e9. doi: 10.1016/j.molcel.2019.09.007. Epub 2019 Oct 2.

γ-6-Phosphogluconolactone, a Byproduct of the Oxidative Pentose Phosphate Pathway, Contributes to AMPK Activation through Inhibition of PP2A.

Author information

1
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
2
Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
3
Department of Chemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
4
Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois 60637, USA.
5
University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
6
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
7
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
8
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
9
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: jchen@emory.edu.

Abstract

The oxidative pentose phosphate pathway (oxiPPP) contributes to cell metabolism through not only the production of metabolic intermediates and reductive NADPH but also inhibition of LKB1-AMPK signaling by ribulose-5-phosphate (Ru-5-P), the product of the third oxiPPP enzyme 6-phosphogluconate dehydrogenase (6PGD). However, we found that knockdown of glucose-6-phosphate dehydrogenase (G6PD), the first oxiPPP enzyme, did not affect AMPK activation despite decreased Ru-5-P and subsequent LKB1 activation, due to enhanced activity of PP2A, the upstream phosphatase of AMPK. In contrast, knockdown of 6PGD or 6-phosphogluconolactonase (PGLS), the second oxiPPP enzyme, reduced PP2A activity. Mechanistically, knockdown of G6PD or PGLS decreased or increased 6-phosphogluconolactone level, respectively, which enhanced the inhibitory phosphorylation of PP2A by Src. Furthermore, γ-6-phosphogluconolactone, an oxiPPP byproduct with unknown function generated through intramolecular rearrangement of δ-6-phosphogluconolactone, the only substrate of PGLS, bound to Src and enhanced PP2A recruitment. Together, oxiPPP regulates AMPK homeostasis by balancing the opposing LKB1 and PP2A.

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PMID:
31586547
PMCID:
PMC6925637
[Available on 2020-12-19]
DOI:
10.1016/j.molcel.2019.09.007

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