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Hydrogen sulfide coordinates glucose metabolism switch through destabilizing tetrameric pyruvate kinase M2

Rong-Hsuan Wang1, Pin-Ru Chen2, Yue-Ting Chen2

  • 1Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.

Nature Communications
|August 28, 2024
PubMed

Insights

Hydrogen sulfide (H2S) inactivates pyruvate kinase M2 (PKM2) through sulfhydration, promoting cancer growth. Inhibiting PKM2 sulfhydration could be a novel therapeutic strategy for targeting cancer metabolism.

Area of Science:

  • Biochemistry
  • Cancer Biology
  • Metabolic Pathways

Background:

  • Cancer cells exhibit altered glucose metabolism, favoring aerobic glycolysis over oxidative phosphorylation.
  • Pyruvate kinase M2 (PKM2) activity is reduced in cancer, diverting metabolites towards macromolecule synthesis for proliferation.

Purpose of the Study:

  • To investigate the role of hydrogen sulfide (H2S) in regulating PKM2 activity and its impact on cancer metabolism.
  • To explore the potential of targeting PKM2 sulfhydration as a cancer therapy.

Main Methods:

  • Investigated the effect of H2S on PKM2 tetramer stability and enzyme activity.
  • Utilized site-directed mutagenesis (C326S) to block PKM2 sulfhydration.
  • Determined the crystal structure of the PKM2-C326S mutant.
  • Assessed the impact of PKM2-C326S on glucose metabolism and tumor growth in cancer cells.

Main Results:

  • H2S destabilizes PKM2 tetramers into monomers/dimers via sulfhydration at cysteine residues, particularly C326.
  • PKM2 sulfhydration reduces enzyme activity and enhances PKM2-mediated transcriptional activation.
  • Blocking C326 sulfhydration stabilizes PKM2 tetramers and shifts cancer cell metabolism towards mitochondrial respiration.
  • The PKM2-C326S mutant significantly inhibits tumor growth.

Conclusions:

  • PKM2 sulfhydration by H2S promotes tumorigenesis by altering cancer metabolism.
  • Inhibiting PKM2 sulfhydration represents a potential therapeutic strategy for targeting cancer metabolism.

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