S-adenosyl-homocysteine is a weakly bound inhibitor for a flaviviral methyltransferase.
S-adenosyl-homocysteine is a weakly bound inhibitor for a flaviviral methyltransferase.
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DOI：
10.1371/journal.pone.0076900
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Chen H;Zhou B;Brecher M;Banavali N;Jones SA;Li Z;Zhang J;Nag D;Kramer LD;Ghosh AK;Li H
甲基转移酶（MTase）催化甲基从s -腺苷-蛋氨酸（AdoMet）转移到病毒RNA，并产生s -腺苷-同型半胱氨酸（AdoHcy）作为副产物，对许多重要的人类病原体黄病毒的生命周期至关重要。本文研究了几种adohcy衍生物对黄病毒MTase的抑制作用。出乎意料的是，我们发现AdoHcy本身即使在高浓度下也几乎不能抑制黄病毒MTase的活性。AdoHcy在细胞培养中也显示不抑制病毒生长。结合研究证实，AdoHcy对MTase的结合亲和力远低于AdoMet辅助因子或天然AdoMet类似物抑制剂sininefungin （SIN）。AdoMet是一种带正电的分子，而SIN与AdoHcy类似，都是不带电的，只是有一个额外的胺基，可以与MTase进行额外的静电接触。分子力学泊松-玻尔兹曼溶液面积分析表明，对AdoHcy和SIN与MTase结合的分析表明，SIN更强的结合可能不是直接由于该胺基的相互作用，而是由于其存在导致的SIN结合的分布差异。结果表明，使用SIN作为支架可以设计出更好的MTase抑制剂，而不是AdoHcy。
The methyltransferase enzyme (MTase), which catalyzes the transfer of a methyl group from S-adenosyl-methionine (AdoMet) to viral RNA, and generates S-adenosyl-homocysteine (AdoHcy) as a by-product, is essential for the life cycle of many significant human pathogen flaviviruses. Here we investigated inhibition of the flavivirus MTase by several AdoHcy-derivatives. Unexpectedly we found that AdoHcy itself barely inhibits the flavivirus MTase activities, even at high concentrations. AdoHcy was also shown to not inhibit virus growth in cell-culture. Binding studies confirmed that AdoHcy has a much lower binding affinity for the MTase than either the AdoMet co-factor, or the natural AdoMet analog inhibitor sinefungin (SIN). While AdoMet is a positively charged molecule, SIN is similar to AdoHcy in being uncharged, and only has an additional amine group that can make extra electrostatic contacts with the MTase. Molecular Mechanics Poisson-Boltzmann Sovation Area analysis on AdoHcy and SIN binding to the MTase suggests that the stronger binding of SIN may not be directly due to interactions of this amine group, but due to distributed differences in SIN binding resulting from its presence. The results suggest that better MTase inhibitors could be designed by using SIN as a scaffold rather than AdoHcy.
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影响因子：
3.7
作者：
Chung, Ka Yan;Dong, Hongping;Lim, Siew Pheng
通讯作者：
Lim, Siew Pheng
DOI：
10.1016/s0378-4347(00)85094-x
发表时间：
1983-01-01
期刊：
JOURNAL OF CHROMATOGRAPHY
影响因子：
--
作者：
BROOKS, JB;KUNO, G;WYCOFF, BJ
通讯作者：
WYCOFF, BJ
影响因子：
4.8
作者：
Dong, Hongping;Liu, Lihui;Li, Hongmin
通讯作者：
Li, Hongmin
影响因子：
5.6
作者：
Geiss, Brian J.;Thompson, Aaron A.;Andrews, Andrew J.;Sons, Robert L.;Gari, Hamid H.;Keenan, Susan M.;Peersen, Olve B.
通讯作者：
Peersen, Olve B.
影响因子：
4.4
作者：
FELLER, SE;ZHANG, YH;BROOKS, BR
通讯作者：
BROOKS, BR