Hydrogen sulfide coordinates glucose metabolism switch through destabilizing tetrameric pyruvate kinase M2 PMID: 39198443

ADC Targets in Oncology

2026-04-10

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

Nat Commun. 2024 Aug 29;15(1):7463. doi: 10.1038/s41467-024-51875-9.

Rong-Hsuan Wang ¹ , Pin-Ru Chen ² , Yue-Ting Chen ² , Yi-Chang Chen ² , Yu-Hsin Chu ¹ , Chia-Chen Chien ¹ , Po-Chen Chien ¹ , Shao-Yun Lo ¹ , Zhong-Liang Wang ¹ , Min-Chen Tsou ¹ , Ssu-Yu Chen ¹ , Guang-Shen Chiu ¹ , Wen-Ling Chen ³ , Yi-Hsuan Wu ⁴ , Lily Hui-Ching Wang ⁴ ⁵ ⁶ , Wen-Ching Wang ⁴ ⁷ , Shu-Yi Lin ⁸ , Hsing-Jien Kung ⁹ , Lu-Hai Wang ¹⁰ , Hui-Chun Cheng ¹¹ ¹² , Kai-Ti Lin ¹³ ¹⁴ ¹⁵

Affiliations

1. Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.
2. Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan.
3. Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan.
4. Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.
5. Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan.
6. School of Medicine, National Tsing Hua University, Hsinchu, Taiwan.
7. Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
8. Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Taiwan.
9. College of Medical Science and Technology, PhD Program for Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
10. Chiese Medicine Research Center, and Institute of Integrated Medicine, China Medical University, Taichung City, Taiwan. [email protected].
11. Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan. [email protected].
12. Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan. [email protected].
13. Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan. [email protected].
14. Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan. [email protected].
15. Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan. [email protected].

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.