Inhibition of Zn(II) binding type IA topoisomerases by organomercury compounds and Hg(II).
Inhibition of Zn(II) binding type IA topoisomerases by organomercury compounds and Hg(II).
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DOI：
10.1371/journal.pone.0120022
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Tse-Dinh YC
中科院分区：
文献类型：
--
作者：
Cheng B;Annamalai T;Sandhaus S;Bansod P;Tse-Dinh YC
IA型拓扑异构酶活性对于通过酶介导的瞬时单链DNA断裂来解决DNA拓扑屏障是必不可少的。拓扑异构酶DNA切割产物的积累可导致细胞死亡或基因组重排。许多抗菌和抗癌药物作为拓扑异构酶毒物抑制剂，与拓扑异构酶共价中间体形成稳定的三元复合物，因此需要鉴定IA型拓扑异构酶的此类抑制剂。在这里，我们报告，有机汞化合物被确定在荧光为基础的筛选NIH多样性的小分子拓扑异构酶抑制剂，可以增加鼠疫耶尔森菌拓扑异构酶I的DNA裂解产物。这些有机汞化合物在大肠杆菌拓扑异构酶I的基于凝胶的测定中证实了松弛活性的抑制和DNA切割产物的积累。汞（II），但不作为（III），也可以针对半胱氨酸，形成多个锌（II）结合四-半胱氨酸基序中发现的这些细菌拓扑异构酶I的C-末端结构域的松弛活性抑制。结核分枝杆菌拓扑异构酶I活性对Hg（II）或有机汞化合物不敏感，因为没有Zn（II）结合半胱氨酸。具有Zn（II）结合结构域的IA型拓扑异构酶在Hg（II）或有机汞化合物的干扰下仍能切割DNA，这一点具有重要意义。人类Top3α和Top3β中存在的Zn（II）结合结构域可能是有毒金属和有机金属配合物的潜在靶点，对基因组的稳定性和发育具有潜在影响。
Type IA topoisomerase activities are essential for resolving DNA topological barriers via an enzyme-mediated transient single strand DNA break. Accumulation of topoisomerase DNA cleavage product can lead to cell death or genomic rearrangement. Many antibacterial and anticancer drugs act as topoisomerase poison inhibitors that form stabilized ternary complexes with the topoisomerase covalent intermediate, so it is desirable to identify such inhibitors for type IA topoisomerases. Here we report that organomercury compounds were identified during a fluorescence based screening of the NIH diversity set of small molecules for topoisomerase inhibitors that can increase the DNA cleavage product of Yersinia pestis topoisomerase I. Inhibition of relaxation activity and accumulation of DNA cleavage product were confirmed for these organomercury compounds in gel based assays of Escherichia coli topoisomerase I. Hg(II), but not As(III), could also target the cysteines that form the multiple Zn(II) binding tetra-cysteine motifs found in the C-terminal domains of these bacterial topoisomerase I for relaxation activity inhibition. Mycobacterium tuberculosis topoisomerase I activity is not sensitive to Hg(II) or the organomercury compounds due to the absence of the Zn(II) binding cysteines. It is significant that the type IA topoisomerases with Zn(II) binding domains can still cleave DNA when interfered by Hg(II) or organomercury compounds. The Zn(II) binding domains found in human Top3α and Top3β may be potential targets of toxic metals and organometallic complexes, with potential consequence on genomic stability and development.
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影响因子：
25
作者：
Xu, Dongyi;Shen, Weiping;Guo, Rong;Xue, Yutong;Peng, Wei;Sima, Jian;Yang, Jay;Sharov, Alexei;Srikantan, Subramanya;Yang, Jiandong;Fox, David, III;Qian, Yong;Martindale, Jennifer L.;Piao, Yulan;Machamer, James;Joshi, Samit R.;Mohanty, Subhasis;Shaw, Albert C.;Lloyd, Thomas E.;Brown, Grant W.;Ko, Minoru S. H.;Gorospe, Myriam;Zou, Sige;Wang, Weidong
通讯作者：
Wang, Weidong
影响因子：
14.9
作者：
Narula G;Tse-Dinh YC
通讯作者：
Tse-Dinh YC
影响因子：
3.9
作者：
Kitchin, Kirk T.;Wallace, Kathleen
通讯作者：
Wallace, Kathleen
DOI：
10.1016/s0006-291x(86)80564-2
发表时间：
1986-07-31
影响因子：
3.1
作者：
KARLOVSKY, P
通讯作者：
KARLOVSKY, P
影响因子：
25
作者：
Stoll, Georg;Pietilainen, Olli P. H.;Linder, Bastian;Suvisaari, Jaana;Brosi, Cornelia;Hennah, William;Leppa, Virpi;Torniainen, Minna;Ripatti, Samuli;Ala-Mello, Sirpa;Plottner, Oliver;Rehnstrom, Karola;Tuulio-Henriksson, Annamari;Varilo, Teppo;Tallila, Jonna;Kristiansson, Kati;Isohanni, Matti;Kaprio, Jaakko;Eriksson, Johan G.;Raitakari, Olli T.;Lehtimaki, Terho;Jarvelin, Marjo-Riitta;Salomaa, Veikko;Hurles, Matthew;Stefansson, Hreinn;Peltonen, Leena;Sullivan, Patrick F.;Paunio, Tiina;Lonnqvist, Jouko;Daly, Mark J.;Fischer, Utz;Freimer, Nelson B.;Palotie, Aarno
通讯作者：
Palotie, Aarno