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Acyl-CoA dehydrogenase long chain (ACADL) is a target protein of stylissatin A, an anti-inflammatory cyclic heptapeptide

The Journal of Antibiotics volume 73, pages 589–592 (2020)Cite this article

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Abstract

Stylissatin A (SA) is a cyclic heptapeptide isolated from the marine sponge Stylissa massa. SA shows anti-inflammatory activity against lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophage cells, but the detailed mechanism of action remains unclear. Here we report that d-Tyr1-tBuSA, a more potent SA derivative, inhibited production of the proinflammatory cytokines Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in LPS-stimulated RAW264.7 cells (EC50 = 1.4 and 5.9 μM, respectively). This compound also inhibited the LPS-stimulated expression of inducible nitric oxide synthase (iNOS) at 20 μM. Using a biotin derivative of SA, acyl-CoA dehydrogenase long chain (ACADL) was identified as a target protein of SA and its derivatives. It is proposed that SA and its derivatives might suppress the β-oxidation of fatty acids by ACADL, and the accumulation of fatty acids on macrophages would inhibit the nuclear factor-kappa B (NF-κB) signaling pathway and iNOS expression to show anti-inflammatory activity. Our research might provide a new mechanism of inflammation in macrophages, and contribute to the development of treatments for inflammatory diseases.

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Acknowledgements

This work is supported in part by JSPS grants (18H04613 and 19H02839 to MK and 26242073 to HK) and JSPS A3 Foresight Program. Support was also provided by Naito Foundation and Yamada Foundation.

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Authors and Affiliations

  1. Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba, 305-8571, Japan

    Menghua Zhang, Taiki Sunaba, Kazunori Sasaki & Hideo Kigoshi

  2. PhD Program in Human Biology, School of Integrative and Global Majors (SIGMA), University of Tsukuba, Tsukuba, 305-8577, Japan

    Menghua Zhang

  3. Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, 464-8601, Japan

    Yiting Sun, Takahiro Shibata & Masaki Kita

  4. Interdisciplinary Research Center for Catalytic Chemistry, National Institute of Advanced Industrial Science and Technology, Tsukuba, 305-8565, Japan

    Kazunori Sasaki

  5. Graduate School of Life and Environmental Sciences, and Alliance for Research on North Africa (ARENA), University of Tsukuba, Tsukuba, 305-8577, Japan

    Hiroko Isoda

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  1. Menghua Zhang
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  2. Taiki Sunaba
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Correspondence to Hideo Kigoshi or Masaki Kita.

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Dedicated to Professor William Fenical in recognition of his contributions to marine derived secondary metabolites.

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Zhang, M., Sunaba, T., Sun, Y. et al. Acyl-CoA dehydrogenase long chain (ACADL) is a target protein of stylissatin A, an anti-inflammatory cyclic heptapeptide. J Antibiot 73, 589–592 (2020). https://doi.org/10.1038/s41429-020-0322-5

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