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

Author

Listed:
  • Rong-Hsuan Wang

    (National Tsing Hua University)

  • Pin-Ru Chen

    (National Tsing Hua University)

  • Yue-Ting Chen

    (National Tsing Hua University)

  • Yi-Chang Chen

    (National Tsing Hua University)

  • Yu-Hsin Chu

    (National Tsing Hua University)

  • Chia-Chen Chien

    (National Tsing Hua University)

  • Po-Chen Chien

    (National Tsing Hua University)

  • Shao-Yun Lo

    (National Tsing Hua University)

  • Zhong-Liang Wang

    (National Tsing Hua University)

  • Min-Chen Tsou

    (National Tsing Hua University)

  • Ssu-Yu Chen

    (National Tsing Hua University)

  • Guang-Shen Chiu

    (National Tsing Hua University)

  • Wen-Ling Chen

    (National Health Research Institutes)

  • Yi-Hsuan Wu

    (National Tsing Hua University)

  • Lily Hui-Ching Wang

    (National Tsing Hua University
    National Tsing Hua University
    National Tsing Hua University)

  • Wen-Ching Wang

    (National Tsing Hua University
    National Tsing Hua University)

  • Shu-Yi Lin

    (National Health Research Institutes)

  • Hsing-Jien Kung

    (Taipei Medical University)

  • Lu-Hai Wang

    (China Medical University)

  • Hui-Chun Cheng

    (National Tsing Hua University
    National Tsing Hua University)

  • Kai-Ti Lin

    (National Tsing Hua University
    National Tsing Hua University
    National Tsing Hua University)

Abstract

Most cancer cells reprogram their glucose metabolic pathway from oxidative phosphorylation to aerobic glycolysis for energy production. By reducing enzyme activity of pyruvate kinase M2 (PKM2), cancer cells attain a greater fraction of glycolytic metabolites for macromolecule synthesis needed for rapid proliferation. Here we demonstrate that hydrogen sulfide (H2S) destabilizes the PKM2 tetramer into monomer/dimer through sulfhydration at cysteines, notably at C326, leading to reduced PKM2 enzyme activity and increased PKM2-mediated transcriptional activation. Blocking PKM2 sulfhydration at C326 through amino acid mutation stabilizes the PKM2 tetramer and crystal structure further revealing the tetramer organization of PKM2-C326S. The PKM2-C326S mutant in cancer cells rewires glucose metabolism to mitochondrial respiration, significantly inhibiting tumor growth. In this work, we demonstrate that PKM2 sulfhydration by H2S inactivates PKM2 activity to promote tumorigenesis and inhibiting this process could be a potential therapeutic approach for targeting cancer metabolism.

Suggested Citation

  • Rong-Hsuan Wang & Pin-Ru Chen & Yue-Ting Chen & Yi-Chang Chen & Yu-Hsin Chu & Chia-Chen Chien & Po-Chen Chien & Shao-Yun Lo & Zhong-Liang Wang & Min-Chen Tsou & Ssu-Yu Chen & Guang-Shen Chiu & Wen-Lin, 2024. "Hydrogen sulfide coordinates glucose metabolism switch through destabilizing tetrameric pyruvate kinase M2," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51875-9
    DOI: 10.1038/s41467-024-51875-9
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    References listed on IDEAS

    as
    1. Jing-Xiang Wu & Yun-Sheng Cheng & Jue Wang & Lei Chen & Mei Ding & Jia-Wei Wu, 2015. "Structural insight into the mechanism of synergistic autoinhibition of SAD kinases," Nature Communications, Nature, vol. 6(1), pages 1-12, December.
    2. Barbara Chaneton & Petra Hillmann & Liang Zheng & Agnès C. L. Martin & Oliver D. K. Maddocks & Achuthanunni Chokkathukalam & Joseph E. Coyle & Andris Jankevics & Finn P. Holding & Karen H. Vousden & C, 2012. "Serine is a natural ligand and allosteric activator of pyruvate kinase M2," Nature, Nature, vol. 491(7424), pages 458-462, November.
    3. Yuhui Jiang & Yugang Wang & Ting Wang & David H. Hawke & Yanhua Zheng & Xinjian Li & Qin Zhou & Sadhan Majumder & Erfei Bi & David X. Liu & Suyun Huang & Zhimin Lu, 2014. "PKM2 phosphorylates MLC2 and regulates cytokinesis of tumour cells," Nature Communications, Nature, vol. 5(1), pages 1-14, December.
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