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A chemical catalyst enabling histone acylation with endogenous acyl-CoA

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  • Misuzu Habazaki

    (The University of Tokyo, 7-3-1 Hongo)

  • Shinsuke Mizumoto

    (The University of Tokyo, 7-3-1 Hongo)

  • Hidetoshi Kajino

    (The University of Tokyo, 7-3-1 Hongo)

  • Tomoya Kujirai

    (The University of Tokyo)

  • Hitoshi Kurumizaka

    (The University of Tokyo)

  • Shigehiro A. Kawashima

    (The University of Tokyo, 7-3-1 Hongo)

  • Kenzo Yamatsugu

    (The University of Tokyo, 7-3-1 Hongo)

  • Motomu Kanai

    (The University of Tokyo, 7-3-1 Hongo)

Abstract

Life emerges from a network of biomolecules and chemical reactions catalyzed by enzymes. As enzyme abnormalities are often connected to various diseases, a chemical catalyst promoting physiologically important intracellular reactions in place of malfunctional endogenous enzymes would have great utility in understanding and treating diseases. However, research into such small-molecule chemical enzyme surrogates remains limited, due to difficulties in developing a reactive catalyst capable of activating inert cellular metabolites present at low concentrations. Herein, we report a small-molecule catalyst, mBnA, as a surrogate for a histone acetyltransferase. A hydroxamic acid moiety of suitable electronic characteristics at the catalytic site, paired with a thiol-thioester exchange process, enables mBnA to activate endogenous acyl-CoAs present in low concentrations and promote histone lysine acylations in living cells without the addition of exogenous acyl donors. An enzyme surrogate utilizing cellular metabolites will be a unique tool for elucidation of and synthetic intervention in the chemistry of life and disease.

Suggested Citation

  • Misuzu Habazaki & Shinsuke Mizumoto & Hidetoshi Kajino & Tomoya Kujirai & Hitoshi Kurumizaka & Shigehiro A. Kawashima & Kenzo Yamatsugu & Motomu Kanai, 2023. "A chemical catalyst enabling histone acylation with endogenous acyl-CoA," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41426-z
    DOI: 10.1038/s41467-023-41426-z
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    References listed on IDEAS

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    1. Laura Pasqualucci & David Dominguez-Sola & Annalisa Chiarenza & Giulia Fabbri & Adina Grunn & Vladimir Trifonov & Lawryn H. Kasper & Stephanie Lerach & Hongyan Tang & Jing Ma & Davide Rossi & Amy Chad, 2011. "Inactivating mutations of acetyltransferase genes in B-cell lymphoma," Nature, Nature, vol. 471(7337), pages 189-195, March.
    2. He Huang & Di Zhang & Yi Wang & Mathew Perez-Neut & Zhen Han & Y. George Zheng & Quan Hao & Yingming Zhao, 2018. "Lysine benzoylation is a histone mark regulated by SIRT2," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
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