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Histone deacetylase 10 structure and molecular function as a polyamine deacetylase

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  • Yang Hai

    (Roy and Diana Vagelos Laboratories, University of Pennsylvania
    Present address: Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, California 90095, USA)

  • Stephen A. Shinsky

    (Roy and Diana Vagelos Laboratories, University of Pennsylvania)

  • Nicholas J. Porter

    (Roy and Diana Vagelos Laboratories, University of Pennsylvania)

  • David W. Christianson

    (Roy and Diana Vagelos Laboratories, University of Pennsylvania)

Abstract

Cationic polyamines such as spermidine and spermine are critical in all forms of life, as they regulate the function of biological macromolecules. Intracellular polyamine metabolism is regulated by reversible acetylation and dysregulated polyamine metabolism is associated with neoplastic diseases such as colon cancer, prostate cancer and neuroblastoma. Here we report that histone deacetylase 10 (HDAC10) is a robust polyamine deacetylase, using recombinant enzymes from Homo sapiens (human) and Danio rerio (zebrafish). The 2.85 Å-resolution crystal structure of zebrafish HDAC10 complexed with a transition-state analogue inhibitor reveals that a glutamate gatekeeper and a sterically constricted active site confer specificity for N8-acetylspermidine hydrolysis and disfavour acetyllysine hydrolysis. Both HDAC10 and spermidine are known to promote cellular survival through autophagy. Accordingly, this work sets a foundation for studying the chemical biology of autophagy through the structure-based design of inhibitors that may also serve as new leads for cancer chemotherapy.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15368
    DOI: 10.1038/ncomms15368
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    Cited by:

    1. 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.
    2. Leonie G. Graf & Carlos Moreno-Yruela & Chuan Qin & Sabrina Schulze & Gottfried J. Palm & Ole Schmöker & Nancy Wang & Dianna M. Hocking & Leila Jebeli & Britta Girbardt & Leona Berndt & Babett Dörre &, 2024. "Distribution and diversity of classical deacylases in bacteria," Nature Communications, Nature, vol. 15(1), pages 1-31, December.

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