Neplanocin A. A potent inhibitor of S-adenosylhomocysteine hydrolase and of vaccinia virus multiplication in mouse L929 cells.
Neplanocin A. A potent inhibitor of S-adenosylhomocysteine hydrolase and of vaccinia virus multiplication in mouse L929 cells.
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DOI：
10.1016/s0021-9258(17)43053-5
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发表时间：
1984-04
期刊：
影响因子：
--
通讯作者：
R. Borchardt;B. Keller;U. Patel-Thombre
中科院分区：
文献类型：
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作者：
R. Borchardt;B. Keller;U. Patel-Thombre
NePlanocin A是一种新型的腺苷的环戊烯类似物，是一种天然存在的抗生素，在小鼠体内对L1210白血病具有显著的抗肿瘤活性(Yaginuma，S.，Muto，N.，Tsujino，M.，Suate，Y.，Hayashi，M.和Otani，M.(1981)J.34、359-366)。在本研究中，我们证明奈普诺菌素A也是S-同型半胱氨酸水解酶(EC3.3.1.1)的有效抑制剂，对纯化的牛肝酶的Ki为8.39 nM。奈普罗星A对ADOHcy水解酶的明显不可逆失活分析表明，该药物是一种紧密结合的抑制剂，表现出一个分子的抑制剂对一个分子的酶(四聚体)的化学计量比。此外，我们还发现奈普诺菌素A对痘苗病毒(WR)在小鼠L细胞单层培养中的增殖有很强的抑制作用。浓度低至0.5微米和1.0微米的药物对菌斑形成的抑制率分别为84%和95%，而对宿主细胞的毒性很小。奈普诺菌素A抑制病毒增殖的同时，感染细胞中的ADOHcy水解酶活性迅速受到抑制，随后细胞内ADOHcy/S-腺苷蛋氨酸比率增加了10倍。这些发现表明，该化合物的抗病毒作用可能与抑制S-腺苷甲硫氨酸依赖的大分子甲基化反应有关，这些甲基化反应是产生新的病毒颗粒(如病毒信使核糖核酸)所必需的。
Neplanocin A, a novel cyclopentenyl analog of adenosine, is a naturally occurring antibiotic which exhibits significant antitumor activity against L1210 leukemia in mice (Yaginuma, S., Muto, N., Tsujino, M., Sudate, Y., Hayashi, M., and Otani, M. (1981) J. Antibiot. 34, 359-366). In the present study we demonstrate that neplanocin A is also a potent inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase (EC 3.3.1.1) having a Ki of 8.39 nM for the purified bovine liver enzyme. Analysis of the apparent irreversible inactivation of AdoHcy hydrolase by neplanocin A indicates that the drug is a tight binding inhibitor, exhibiting a stoichiometry of one molecule of inhibitor to one molecule (tetramer) of enzyme. In addition, we show that neplanocin A is a potent inhibitor of vaccinia virus (WR) multiplication in monolayer cultures of mouse L-cells. Concentrations of the drug as low as 0.5 and 1.0 microM in the culture medium produce 84 and 95% inhibition of plaque formation, respectively, while exhibiting little toxicity to the host cells. The inhibition of virus multiplication by neplanocin A coincides with a rapid inhibition of AdoHcy hydrolase activity in the infected cells and a subsequent 10-fold increase in the intracellular AdoHcy/S-adenosylmethionine ratio. These findings suggest that the antiviral actions of this compound may be related to an inhibition of S-adenosylmethionine-dependent macromolecular methylation reactions which are essential to the production of new virus particles (e.g. viral messenger RNA).