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Subtype selective substrates for histone deacetylases.

Birgit Heltweg1, Franck Dequiedt, Brett L Marshall

  • 1Department of Pharmaceutical and Medicinal Chemistry, Westfälische Wilhelms-Universität Münster, Hittorfstrasse 58-62, 48149 Münster, Germany.

Journal of Medicinal Chemistry
|October 1, 2004
PubMed
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Researchers explored how molecule shape affects histone deacetylase (HDAC) activity using synthetic substrates. Larger groups on lysine-derived molecules reduced activity in HDAC classes I and II, but not class III, revealing enzyme subtype selectivity.

Area of Science:

  • Biochemistry
  • Enzymology
  • Molecular Biology

Background:

  • Histone deacetylases (HDACs) are crucial epigenetic regulators involved in various cellular processes.
  • Understanding the structural basis of HDAC activity is essential for developing targeted therapies.

Purpose of the Study:

  • To investigate the steric requirements for deacylation by different classes of HDACs.
  • To establish structure-reactivity relationships for small molecule substrates with HDACs.
  • To explore the potential of these substrates for predicting HDAC inhibitor subtype selectivity.

Main Methods:

  • Synthesis of lysine-derived small molecule substrates with varying acyl substituents.
  • Enzymatic assays using rat liver, human HeLa, and recombinant class I, II, and III HDACs (including SIRT1).

Related Experiment Videos

  • Analysis of substrate conversion rates and subtype selectivity using recombinant human HDACs (1, 3, and 6).

    • Main Results:

    • A benzyloxycarbonyl substituent on the alpha-amino group enhanced substrate conversion.
    • Larger lipophilic acyl substituents at the epsilon-amino position significantly decreased conversion by class I and II HDACs.
    • Class III HDAC (SIRT1) showed greater tolerance to larger acyl substituents compared to class I and II.
    • Distinct subtype selectivity was observed for human HDACs 1, 3, and 6 with the synthesized substrates.
    • Substrate selectivity correlated with the ability to predict HDAC inhibitor subtype selectivity.

    Conclusions:

    • Steric bulk of acyl substituents plays a critical role in modulating deacylation activity across different HDAC classes.
    • The synthesized small molecule substrates exhibit specific subtype selectivity for human HDACs.
    • These substrates offer a valuable tool for predicting the subtype selectivity of HDAC inhibitors, aiding in drug development.