DIFFERENTIAL INHIBITION OF HISTONE AND POLYAMINE ACETYLASES BY MULTISUBSTRATE ANALOGS
DIFFERENTIAL INHIBITION OF HISTONE AND POLYAMINE ACETYLASES BY MULTISUBSTRATE ANALOGS
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DOI：
10.1021/bi00313a036
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发表时间：
1984-01-01
期刊：
影响因子：
2.9
通讯作者：
PEGG, AE
中科院分区：
文献类型：
--
作者：
ERWIN, BG;PERSSON, L;PEGG, AE
哺乳动物细胞含有许多催化多胺和组蛋白乙酰化的酶，包括诱导型亚精胺/精胺 N1-乙酰转移酶，它可能在调节多胺相互转化中发挥关键作用。进行本实验是为了提供一种将该酶与其他多胺/组蛋白乙酰化酶区分开的方法，并测试是否可以获得其活性的特异性抑制剂。兔抗同质大鼠肝亚精胺/精胺N1-乙酰转移酶抗血清对大鼠肝脏粗核提取物的活性没有影响，表明其亚精胺乙酰化能力与肝毒素诱导的胞质亚精胺/精胺N1-乙酰转移酶无关。通过乙酸键将各种多胺连接到 CoA 上，制备了潜在的多底物类似物，并作为亚精胺和组蛋白乙酰化的潜在抑制剂进行了测试。这些多胺衍生物作为粗核提取物的组蛋白或亚精胺乙酰化抑制剂的效力几乎没有差异，粗核提取物似乎含有至少2种这样的活性，一种被20-30μM完全抑制，另一种占总数的50％不受100μM的影响。亚精胺/精胺 N1-乙酰转移酶也被所有衍生物抑制，但对该酶的效力差异很大。来自sym-norspermidine的衍生物是一种非常强的抑制剂，在0.3μM时产生50％的抑制，并且比其他的活性高出1个数量级以上。这些结果与作为多底物类似物的N-[2-(S-CoA)乙酰基]-对称-去甲亚精胺酰胺一致，因为对称-去甲亚精胺是亚精胺/精胺N1-乙酰转移酶的优选底物，其Km (9μM)比亚精胺(130μM)小14倍。比较这些抑制剂对细胞和核提取物的影响对于理解多胺和组蛋白乙酰化酶的生理作用可能很有价值。
Mammalian cells contain a number of enzymes catalyzing the acetylation of polyamines and histones including an inducible spermidine/spermine N1-acetyltransferase which may play a key role in regulating the interconversion of polyamines. The present experiments were carried out in order to provide a method to distinguish this enzyme from other polyamine/histone acetylases and to test whether specific inhibitors of its activity could be obtained. Rabbit antiserum to homogeneous rat liver spermidine/spermine N1-acetyltransferase had no effect on the activity of a crude nuclear extract from rat liver, indicating that its spermidine acetylating capability is not related to the cytosolic spermidine/spermine N1-acetyltransferase induced by hepatotoxins. Potential multisubstrate analogs were prepared by attaching various polyamines to CoA via an acetic acid linkage and tested as potential inhibitors of the acetylation of spermidine and histones. There was little difference in the potency of these polyamine derivatives as inhibitors of histone or spermidine acetylation by the crude nuclear extracts which appeared to contain at least 2 such activities, one inhibited completely by 20-30 .mu.M and the other amounting to 50% of the total being unaffected by 100 .mu.M. Spermidine/spermine N1-acetyltransferase was also inhibited by all the derivatives, but the potency toward this enzyme differed widely. The derivative from sym-norspermidine was a very strong inhibitor, giving 50% inhibition at 0.3 .mu.M, and was more than 1 order of magnitude more active than the others. These results are consistent with N-[2-(S-CoA)acetyl]-sym-norspermidine amide acting as a multisubstrate analogs since sym-norspermidine is a preferred substrate of spermidine/spermine N1-acetyltransferase, having a Km (9 .mu.M) 14 times less than that for spermidine (130 .mu.M). Comparisons of the effects of these inhibitors on cells and nuclear extracts may be valuable in understanding the physiological role of polyamine and histone acetylases.