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 Cheng () and Kai-Ti Lin ()
Additional contact information
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
Wen-Ching Wang: 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
Kai-Ti Lin: National Tsing Hua University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51875-9

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