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Glycolytic flux control by drugging phosphoglycolate phosphatase

Author

Listed:
  • Elisabeth Jeanclos

    (University of Würzburg)

  • Jan Schlötzer

    (University of Würzburg)

  • Kerstin Hadamek

    (University of Würzburg)

  • Natalia Yuan-Chen

    (University of Würzburg)

  • Mohammad Alwahsh

    (Leibniz-Institut für analytische Wissenschaften-ISAS
    University Medical Center Mannheim, Heidelberg University
    Faculty of Pharmacy, Al-Zaytoonah University of Jordan)

  • Robert Hollmann

    (Leibniz-Institut für analytische Wissenschaften-ISAS)

  • Stefanie Fratz

    (University of Würzburg)

  • Dilan Yesilyurt-Gerhards

    (University of Würzburg)

  • Tina Frankenbach

    (University of Würzburg)

  • Daria Engelmann

    (University of Würzburg)

  • Angelika Keller

    (University of Würzburg)

  • Alexandra Kaestner

    (University of Würzburg)

  • Werner Schmitz

    (University of Würzburg)

  • Martin Neuenschwander

    (Leibniz-Forschungsinstitut für Molekulare Pharmakologie-FMP)

  • Roland Hergenröder

    (Leibniz-Institut für analytische Wissenschaften-ISAS)

  • Christoph Sotriffer

    (University of Würzburg)

  • Jens Peter Kries

    (Leibniz-Forschungsinstitut für Molekulare Pharmakologie-FMP)

  • Hermann Schindelin

    (University of Würzburg)

  • Antje Gohla

    (University of Würzburg)

Abstract

Targeting the intrinsic metabolism of immune or tumor cells is a therapeutic strategy in autoimmunity, chronic inflammation or cancer. Metabolite repair enzymes may represent an alternative target class for selective metabolic inhibition, but pharmacological tools to test this concept are needed. Here, we demonstrate that phosphoglycolate phosphatase (PGP), a prototypical metabolite repair enzyme in glycolysis, is a pharmacologically actionable target. Using a combination of small molecule screening, protein crystallography, molecular dynamics simulations and NMR metabolomics, we discover and analyze a compound (CP1) that inhibits PGP with high selectivity and submicromolar potency. CP1 locks the phosphatase in a catalytically inactive conformation, dampens glycolytic flux, and phenocopies effects of cellular PGP-deficiency. This study provides key insights into effective and precise PGP targeting, at the same time validating an allosteric approach to control glycolysis that could advance discoveries of innovative therapeutic candidates.

Suggested Citation

  • Elisabeth Jeanclos & Jan Schlötzer & Kerstin Hadamek & Natalia Yuan-Chen & Mohammad Alwahsh & Robert Hollmann & Stefanie Fratz & Dilan Yesilyurt-Gerhards & Tina Frankenbach & Daria Engelmann & Angelik, 2022. "Glycolytic flux control by drugging phosphoglycolate phosphatase," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34228-2
    DOI: 10.1038/s41467-022-34228-2
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