Glycolytic flux control by drugging phosphoglycolate phosphatase

Elisabeth Jeanclos, Jan Schlötzer, Kerstin Hadamek, Natalia Yuan-Chen, Mohammad Alwahsh, Robert Hollmann, Stefanie Fratz, Dilan Yesilyurt-Gerhards, Tina Frankenbach, Daria Engelmann, Angelika Keller, Alexandra Kaestner, Werner Schmitz, Martin Neuenschwander, Roland Hergenröder, Christoph Sotriffer, Jens Peter Kries, Hermann Schindelin and Antje Gohla ()
Additional contact information
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
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

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34228-2

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