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

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 Ling Chen, Yi Hsuan Wu, Lily Hui Ching Wang, Wen Ching Wang, Shu Yi Lin, Hsing Jien Kung, Lu Hai Wang, Hui Chun ChengKai Ti Lin

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Article number7463
JournalNature Communications
Volume15
Issue number1
DOIs
Publication statusPublished - Dec 2024

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General Physics and Astronomy

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