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Chemoproteomic target deconvolution reveals Histone Deacetylases as targets of (R)-lipoic acid

Author

Listed:
  • Severin Lechner

    (Technical University of Munich)

  • Raphael R. Steimbach

    (Cancer Drug Development, German Cancer Research Center (DKFZ)
    Biosciences Faculty, Heidelberg University)

  • Longlong Wang

    (Friedrich Miescher Institute for Biomedical Research
    Faculty of Sciences, University of Basel)

  • Marshall L. Deline

    (Technical University of Munich)

  • Yun-Chien Chang

    (Technical University of Munich)

  • Tobias Fromme

    (Technical University of Munich
    Technical University of Munich)

  • Martin Klingenspor

    (Technical University of Munich
    Technical University of Munich
    Technical University of Munich)

  • Patrick Matthias

    (Friedrich Miescher Institute for Biomedical Research
    Faculty of Sciences, University of Basel)

  • Aubry K. Miller

    (Cancer Drug Development, German Cancer Research Center (DKFZ)
    German Cancer Consortium (DKTK))

  • Guillaume Médard

    (Technical University of Munich)

  • Bernhard Kuster

    (Technical University of Munich
    German Cancer Consortium (DKTK)
    Technical University of Munich)

Abstract

Lipoic acid is an essential enzyme cofactor in central metabolic pathways. Due to its claimed antioxidant properties, racemic (R/S)-lipoic acid is used as a food supplement but is also investigated as a pharmaceutical in over 180 clinical trials covering a broad range of diseases. Moreover, (R/S)-lipoic acid is an approved drug for the treatment of diabetic neuropathy. However, its mechanism of action remains elusive. Here, we performed chemoproteomics-aided target deconvolution of lipoic acid and its active close analog lipoamide. We find that histone deacetylases HDAC1, HDAC2, HDAC3, HDAC6, HDAC8, and HDAC10 are molecular targets of the reduced form of lipoic acid and lipoamide. Importantly, only the naturally occurring (R)-enantiomer inhibits HDACs at physiologically relevant concentrations and leads to hyperacetylation of HDAC substrates. The inhibition of HDACs by (R)-lipoic acid and lipoamide explain why both compounds prevent stress granule formation in cells and may also provide a molecular rationale for many other phenotypic effects elicited by lipoic acid.

Suggested Citation

  • Severin Lechner & Raphael R. Steimbach & Longlong Wang & Marshall L. Deline & Yun-Chien Chang & Tobias Fromme & Martin Klingenspor & Patrick Matthias & Aubry K. Miller & Guillaume Médard & Bernhard Ku, 2023. "Chemoproteomic target deconvolution reveals Histone Deacetylases as targets of (R)-lipoic acid," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39151-8
    DOI: 10.1038/s41467-023-39151-8
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    References listed on IDEAS

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    1. Xin Li & Sheng Wang & Ying Xie & Hongmei Jiang & Jing Guo & Yixuan Wang & Ziyi Peng & Meilin Hu & Mengqi Wang & Jingya Wang & Qian Li & Yafei Wang & Zhiqiang Liu, 2023. "Deacetylation induced nuclear condensation of HP1γ promotes multiple myeloma drug resistance," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Yang Hai & Stephen A. Shinsky & Nicholas J. Porter & David W. Christianson, 2017. "Histone deacetylase 10 structure and molecular function as a polyamine deacetylase," Nature Communications, Nature, vol. 8(1), pages 1-9, August.
    3. Todd J. Cohen & Andrew W. Hwang & Clark R. Restrepo & Chao-Xing Yuan & John Q. Trojanowski & Virginia M. Y. Lee, 2015. "An acetylation switch controls TDP-43 function and aggregation propensity," Nature Communications, Nature, vol. 6(1), pages 1-13, May.
    4. Wenting Guo & Maximilian Naujock & Laura Fumagalli & Tijs Vandoorne & Pieter Baatsen & Ruben Boon & Laura Ordovás & Abdulsamie Patel & Marc Welters & Thomas Vanwelden & Natasja Geens & Tine Tricot & V, 2017. "HDAC6 inhibition reverses axonal transport defects in motor neurons derived from FUS-ALS patients," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
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