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Nutrient-Based Chemical Library as a Source of Energy Metabolism Modulators

  • Tomoyuki Furuta
    Tomoyuki Furuta
    Institute for Chemical Research and Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto, 611-0011, Japan
  • Yuya Mizukami
    Yuya Mizukami
    Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
  • Lisa Asano
    Lisa Asano
    Institute for Chemical Research and Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto, 611-0011, Japan
    More by Lisa Asano
  • Kenjiro Kotake
    Kenjiro Kotake
    Institute for Chemical Research and Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto, 611-0011, Japan
  • Slava Ziegler
    Slava Ziegler
    Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
  • Hiroki Yoshida
    Hiroki Yoshida
    Institute for Chemical Research and Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto, 611-0011, Japan
  • Mizuki Watanabe
    Mizuki Watanabe
    Institute for Chemical Research and Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto, 611-0011, Japan
  • Shin-ichi Sato
    Shin-ichi Sato
    Institute for Chemical Research and Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto, 611-0011, Japan
  • Herbert Waldmann
    Herbert Waldmann
    Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
  • Makiya Nishikawa*
    Makiya Nishikawa
    Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
    Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
    *E-mail: [email protected]
  • , and 
  • Motonari Uesugi*
    Motonari Uesugi
    Institute for Chemical Research and Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto, 611-0011, Japan
    RIKEN-Max Planck Joint Research Division for Systems Chemical Biology, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
    School of Pharmacy, Fudan University, Shanghai 201203, China
    *E-mail: [email protected]
Cite this: ACS Chem. Biol. 2019, 14, 9, 1860–1865
Publication Date (Web):August 22, 2019
https://doi.org/10.1021/acschembio.9b00444
Copyright © 2019 American Chemical Society

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    Abstract

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    Covalent conjugates of multiple nutrients often exhibit greater biological activities than each individual nutrient and more predictable safety profiles than completely unnatural chemical entities. Here, we report the construction and application of a focused chemical library of 308 covalent conjugates of a variety of small-molecule nutrients. Screening of the library with a reporter gene of sterol regulatory element-binding protein (SREBP), a master regulator of mammalian lipogenesis, led to the discovery of a conjugate of docosahexaenoic acid (DHA), glucosamine, and amino acids as an inhibitor of SREBP (molecule 1, DHG). Mechanistic analyses indicate that molecule 1 impairs the SREBP activity by inhibiting glucose transporters and thereby activating AMP-activated protein kinase (AMPK). Oral administration of molecule 1 suppressed the intestinal absorption of glucose in mice. These results suggest that such synthetic libraries of nutrient conjugates serve as a source of novel chemical tools and pharmaceutical seeds that modulate energy metabolism.

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    Cited By

    This article is cited by 2 publications.

    1. Makoto Kawatani, Harumi Aono, Sayoko Hiranuma, Takeshi Shimizu, Makoto Muroi, Naoko Ogawa, Tomokazu Ohishi, Shun-ichi Ohba, Manabu Kawada, Toshihiko Nogawa, Akiko Okano, Daisuke Hashizume, Hiroyuki Osada. Identification of a Small-Molecule Glucose Transporter Inhibitor, Glutipyran, That Inhibits Cancer Cell Growth. ACS Chemical Biology 2021, 16 (8) , 1576-1586. https://doi.org/10.1021/acschembio.1c00480
    2. Majid Manzoor, Makoto Muroi, Naoko Ogawa, Hiroki Kobayashi, Haruna Nishimura, Danni Chen, Opeyemi B. Fasina, Jianyu Wang, Hiroyuki Osada, Minoru Yoshida, Lan Xiang, Jianhua Qi. Isoquercitrin from Apocynum venetum L. produces an anti-obesity effect on obese mice by targeting C-1-tetrahydrofolate synthase, carbonyl reductase, and glutathione S -transferase P and modification of the AMPK/SREBP-1c/FAS/CD36 signaling pathway in mice in vivo. Food & Function 2022, 13 (21) , 10923-10936. https://doi.org/10.1039/D2FO02438A

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