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Cited by 156Heat shock proteins researchBiochemical and Molecular ResearchCancer, Hypoxia, and Metabolism

Terazosin activates Pgk1 and Hsp90 to promote stress resistance

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Chen, Xinping, Zhao, Chunyue, Li, Xiaolong, Wang, Tao, Li, Yizhou, Cao, Cheng, Ding, Yuehe, Dong, Mengqiu +4 more·2015·Nature Chemical Biology
DOI 10.1038/nchembio.1657PMC PMC4412158
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Abstract

Drugs that can protect against organ damage are urgently needed, especially for diseases such as sepsis and brain stroke. We discovered that terazosin (TZ), a widely marketed α1-adrenergic receptor antagonist, alleviated organ damage and improved survival in rodent models of stroke and sepsis. Through combined studies of enzymology and X-ray crystallography, we discovered that TZ binds a new target, phosphoglycerate kinase 1 (Pgk1), and activates its enzymatic activity, probably through 2,4-diamino-6,7-dimethoxyisoquinoline's ability to promote ATP release from Pgk1. Mechanistically, the ATP generated from Pgk1 may enhance the chaperone activity of Hsp90, an ATPase known to associate with Pgk1. Upon activation, Hsp90 promotes multistress resistance. Our studies demonstrate that TZ has a new protein target, Pgk1, and reveal its corresponding biological effect. As a clinical drug, TZ may be quickly translated into treatments for diseases including stroke and sepsis.

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  • TZ decreases seizure severity most likely by activating PGK1 and subsequently enhancing cellular levels of ATP.

    “most likely by activating PGK1 and subsequently enhancing cellular levels of ATP (Fig. 4J) (Chen et al., 2015).”

    From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Chen et al., 2015

    The Results section ('TZ was an activator of phosphoglycerate kinase 1') reports that low-dose TZ activated Pgk1 and transiently raised ATP in cell lysate. The paper does not report a reduction in seizure severity or establish that ATP levels rose in cells during seizures; its outcomes concern apoptosis, sepsis, and stroke. No page numbers are available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • TZ-mediated activation of PGK1 attenuates neuronal death in multiple animal models of Parkinson's disease.

    “and attenuates neuronal death in multiple animal models of Parkinson’s disease (Cai et al., 2019; Chen et al., 2015; Simmering et al., 2021).”

    From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Chen et al., 2015

    The Results sections report that terazosin activates Pgk1 and that it reduced infarct volume in a rat stroke model, suggesting protection of neural cells. They do not report Parkinson’s disease models, let alone reduced neuronal death in multiple such models. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Terazosin activates PGK1 at much lower concentration, resulting in enhanced production of ATP and pyruvate.

    “it also activates PGK1 at much lower concentration, resulting in enhanced productions of ATP and pyruvate (Fig. 4A) (Cai et al., 2019; Chen et al., 2015; Kokotos et al., 2024)”

    From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Chen et al., 2015

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Cited by

Sorted by citations

Authors
Chen, X., Zhao, C., Li, X., Wang, T., Li, Y., Cao, C., Ding, Y., Dong, M., Finci, L., Wang, J.-H., Li, X., & Liu, L.
Affiliations
  • Capital Medical University (CN)
  • University of Science and Technology of China (CN)
  • Peking University (CN)
  • National Institute of Biological Sciences, Beijing (CN)
Corresponding author
  • Li, Xiaolong
  • Wang, Jia-huai
ORCID
Venue
Nature Chemical Biology
Publisher
Springer Science and Business Media LLC
Published
2014-11-10
Volume
11
Issue
1
Pages
19-25
ISSN
  • 1552-4450 (ISSN-L)
  • 1552-4469
DOI
10.1038/nchembio.1657
PMC
PMC4412158
OpenAlex
W2143464189
Cited by
156
References
3
Citations by year
2026: 22 · 2025: 31 · 2024: 26 · 2023: 17 · 2022: 19 · 2021: 10 · 2020: 7 · 2019: 8 · 2018: 3 · 2017: 3 · 2016: 6 · 2015: 3 · 2014: 1
FWCI
1.64
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Chemical Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
Funders
  • National Natural Science Foundation of China (2013CB530700)
  • Ministry of Education of the People's Republic of China
  • Ministry of Science and Technology of the People's Republic of China (2013CB530700)
  • National Institutes of Health (HL48675)
  • National Heart, Lung, and Blood Institute (HL48675, P01HL103526, P01HL048675)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords
terazosin, PGK1, HSP90, alpha-blockers, stress tolerance, apoptosis, ATP production, glycolysis, stroke, sepsis, drug target identification, chaperone activity, organ damage
MeSH terms
Animals, Cells, Cultured, Models, Molecular, Phosphoglycerate Kinase, Prazosin, Protein Conformation, Stress, Physiological, Cytokines, Apoptosis, Sepsis, HSP90 Heat-Shock Proteins, Infarction, Middle Cerebral Artery, Stroke, Mice, Rats, Adrenergic alpha-1 Receptor Antagonists

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