Subtype selective substrates for histone deacetylases

被引:110
作者
Heltweg, B
Dequiedt, F
Marshall, BL
Branch, C
Yoshida, M
Nishino, N
Verdin, E
Jung, M
机构
[1] Univ Munster, Dept Pharmaceut & Med Chem, D-48149 Munster, Germany
[2] FUSAGx, Mol & Cellular Biol Unit, B-5030 Gembloux, Belgium
[3] Univ Calif San Francisco, Gladstone Inst Virol & Immunol, San Francisco, CA 94141 USA
[4] RIKEN, Chem Genet Lab, Wako, Saitama 3510198, Japan
[5] Kyushu Inst Technol, Dept Appl Chem, Tabata Ku, Kitakyushu, Fukuoka 8048550, Japan
关键词
D O I
10.1021/jm0497592
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:5235 / 5243
页数:9
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