Subtype Selective Substrates For Histone Deacetylases

[en] To probe the steric requirements for deacylation, we synthesized lysine-derived small molecule substrates and examined structure-reactivity relationships with various histone deacetylases. Rat liver, human HeLa, and human recombinant class I and II histone deacetylases (HDACs) as well as human recombinant NAD(+)-dependent SIRT1 (class III enzyme) were used in these studies. A benzyloxycarbonyl substituent on the alpha-amino group yielded the highest conversion rates. Replacing the epsilon-acetyl group with larger lipophilic acyl substituents led to a pronounced decrease in conversion by class I and II enzymes; the class III enzyme displayed a greater tolerance. Incubations with recombinant FLAG-tagged human HDACs 1, 3, and 6 showed a distinct subtype selectivity among small molecule substrates. The subtype selectivity of HDAC inhibitors could be predicted with these substrates and an easily obtainable mixture of HDAC subtypes.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Heltweg, B.

Dequiedt, Franck ; Université de Liège - ULiège > GIGA-Research

Marshall, Bl.

Branch, C.

Yoshida, M.

Nishino, N.

Verdin, Emeline ; Université de Liège - ULiège > Génie chimique - Opérations physiques unitaires

Jung, M.

Language :

English

Title :

Subtype Selective Substrates For Histone Deacetylases

Publication date :

2004

Journal title :

Journal of Medicinal Chemistry

ISSN :

0022-2623

eISSN :

1520-4804

Publisher :

American Chemical Society, Washington, United States - District of Columbia

Volume :

Issue :

Pages :

5235-5243

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 24 December 2010

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Scopus citations^®

120

Scopus citations^®
without self-citations

OpenCitations

106

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