PXD044925

PXD044925 is an original dataset announced via ProteomeXchange.

Title	Hydrogen Sulfide Coordinates Glucose Metabolism Switch through Destabilizing Tetrameric Pyruvate Kinase M2
Description	Cancer cells reprogram their glucose metabolic pathway from oxidative phosphorylation toward aerobic glycolysis. Pyruvate kinase M2 (PKM2), which converts phosphoenolpyruvate (PEP) to pyruvate, is considered the rate-limiting enzyme involved in cancer glucose metabolism. By reducing PKM2 enzyme activity, cancer cells attain a greater fraction of glycolytic metabolites for macromolecule synthesis needed for rapid proliferation. Here we demonstrate that hydrogen sulfide (H2S) destabilizes PKM2 tetramer into dimer/monomer, leading to reduced PKM2 enzyme activity and an increase in the activation of nuclear transcriptional genes mediated by dimeric PKM2. Proteomic profiling of endogenous PKM2 reveals the occurrence of sulfhydration at multiple cysteine residues, notably cysteine 326. Blocking PKM2 sulfhydration at cysteine 326 through amino acid mutation stabilizes PKM2 tetramer and crystal structure further indicating that the tetramer organization of PKM2C326S is different from the currently known T or R states, revealing PKM2C326S as a newly identified intermediate form. The presence of a PKM2C326S mutant in cancer cells effectively rewires glucose metabolism to mitochondrial respiration, resulting in the significant inhibition of tumor growth. Collectively, PKM2 sulfhydration by H2S serves as a glucose metabolic rewiring mechanism in promoting tumorigenesis, and inhibition of PKM2 sulfhydration may be applied as a new therapeutic approach targeting cancer metabolism.
HostingRepository	PRIDE
AnnounceDate	2024-07-09
AnnouncementXML	Submission_2024-07-09_06:32:11.416.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Rong-Hsuan Wang
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	Sulfide; Trioxidation; dihydroxylated residue; methylthiolated residue; Glutathione; S-nitrosyl-L-cysteine; monohydroxylated residue; deamidated residue; L-cysteine persulfide; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap Velos; LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2023-08-29 01:07:06	ID requested
⏵ 1	2024-07-09 06:32:11	announced

Dataset with its publication pending

submitter keyword: Glucose Metabolism,PKM2, LC-MS, Oligomerization, Sulfhydration, Hydrogen Sulfide

Kai-Ti Lin
contact affiliation	Institute of Biotechnology, College of Life Science, National Tsing Hua University, Taiwan Department of Medical Science, National Tsing Hua University, Taiwan
contact email	ktl.lab.nthu@gmail.com
lab head
Rong-Hsuan Wang
contact affiliation	Institute of Biotechnology, College of Life Science, National Tsing Hua University
contact email	rong_hsuan_wang@gapp.nthu.edu.tw
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD044925
     1. Label: PRIDE project
     2. Name: Hydrogen Sulfide Coordinates Glucose Metabolism Switch through Destabilizing Tetrameric Pyruvate Kinase M2