Effect of O6-alkylguanine-DNA alkyltransferase on genotoxicity of epihalohydrins.
Effect of O6-alkylguanine-DNA alkyltransferase on genotoxicity of epihalohydrins.
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DOI：
10.1002/em.20491
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发表时间：
2009-07
影响因子：
2.8
通讯作者：
Pegg, Anthony E.
中科院分区：
文献类型：
--
作者：
Kalapila, Aley G.;Loktionova, Natalia A.;Pegg, Anthony E.
研究了o6 -烷基鸟嘌呤- dna烷基转移酶（AGT）对环氧卤代醇的毒性和致突变性的影响。AGT是一种DNA修复蛋白，通过一步将烷基转移到内部半胱氨酸残基（人类AGT中的Cys145），保护细胞免受基因毒性o6 -烷基鸟嘌呤损伤。这个半胱氨酸受体位点具有高度的反应性，并且上皮溴丙烷很容易与该位点的AGT发生反应，反应性为Br > Cl > f，其卤化物顺序为AGT。细菌细胞中AGT的表达导致上皮溴丙烷的诱变性和细胞毒性大大增加。突变几乎都是G:C到A:T的转变。环氧氯丙烷也增强了agt介导的诱变，但程度低于环氧溴丙烷。体外实验表明，AGT在epibromohydrin的存在下与DNA发生共价交联，这种结合主要发生在Cys145上，在Cys150上发生的程度较小，Cys150也是活性位点口袋内活性较低的残基。发现产生AGT-DNA加合物的两条途径发生。主要的机制是产生AGT-epihalohydrin中间体，AGT的DNA结合特性促进了中间体与DNA的共价反应。第二种途径涉及初始反应性dna -环氧乙基丙烷中间体，随后与AGT反应。我们的研究结果表明，agt介导的遗传毒性的矛盾增加，之前已被证明发生在二卤代烷，二氧化丁二烯和氮芥中，也发生在环氧卤代醇中，这可能有助于它们的毒性和诱变性。
The effect of O6-alkylguanine-DNA alkyltransferase (AGT) on the toxicity and mutagenicity of epihalohydrins was studied. AGT is a DNA repair protein that protects cells from agents that produce genotoxic O6-alkylguanine lesions by transferring the alkyl group to an internal cysteine residue (Cys145 in human AGT) in a single-step. This cysteine acceptor site is highly reactive and epihalohydrins reacted readily with AGT at this site with a halide order of reactivity of Br > Cl > F. AGT expression in bacterial cells caused a very large increase in the mutagenicity and cytotoxicity of epibromohydrin. The mutations were almost all G:C to A:T transitions. Epichlorohydrin also augmented AGT-mediated mutagenesis but to a lesser extent than epibromohydrin. In vitro experiments showed that AGT was covalently cross-linked to DNA in the presence of epibromohydrin and that this conjugation occurred predominantly at Cys145, and to a smaller extent at Cys150, a less reactive residue also located within the active site pocket. Two pathways yielding the AGT-DNA adduct were found to occur. The predominant mechanism results in an AGT-epihalohydrin intermediate, which, facilitated by the DNA binding properties of AGT, then reacts covalently with DNA. The second pathway involves an initial reactive DNA-epihalohydrin intermediate that subsequently reacts with AGT. Our results show that the paradoxical AGT-mediated increase in genotoxicity which has previously been shown to occur with dihaloalkanes, butadiene diepoxide and nitrogen mustards, also occurs with epihalohydrins and is likely to contribute to their toxicity and mutagenicity.
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影响因子：
16.8
作者：
Daniels, DS;Woo, TT;Tainer, JA
通讯作者：
Tainer, JA
影响因子：
8.8
作者：
Chroust, Karel;Pavlova, Martina;Damborsky, Jiri
通讯作者：
Damborsky, Jiri
影响因子：
2.9
作者：
KANUGULA, S;GOODTZOVA, K;PEGG, AE
通讯作者：
PEGG, AE
DOI：
10.1073/pnas.0708058105
发表时间：
2008-03-25
影响因子：
11.1
作者：
Hu, Jie;Ma, Ao;Dinner, Aaron R.
通讯作者：
Dinner, Aaron R.
影响因子：
3.8
作者：
Garibyan, L;Huang, T;Miller, JH
通讯作者：
Miller, JH