MOLECULAR MODELING IN CARCINOGENESIS
致癌作用的分子模型
基本信息
- 批准号:6375844
- 负责人:
- 金额:$ 24.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1989
- 资助国家:美国
- 起止时间:1989-12-01 至 2003-08-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Benzo{a}pyrene is a potent mutagen/carcinogen that is metabolically activated inside cells, including to its (+)-anti-7,8-diol-9,10- epoxide [(+)-anti-B[a]PDE, which gives DNA adducts, principally a N2-dG. We showed that (+)-anti-B[a]PDE able to induce such a diverse array of mutations? Base substitution mutations predominate, and principally occur at G:C base pairs, where GC->TA, GC->AT and GC->CG are all significant (57%, 23%, 20%, respectively). We have done molecular biological/mutagenesis work to show that (+)-trans-antiB[a]P-n2-Gus is capable of inducing a preponderance of G->T mutations (> approximately 95 percent) in 5'-TGC sequences, or a preponderance of G->A mutations (->approximately 95 percent) in a 5'-AGA sequence. This raises the question: how can a single entity [i.e., (+)-trans-anti-B[a]P-N2-Gua] induce a different pattern of mutations depending on sequence context? Our working hypothesis has been that adduct mutational complexity is due to adduct conformational complexity, and that adduct conformation and, thereby, mutation is controlled by various factors, notably, DNA sequence context. To study adduct conformation, we did molecular modeling, and found that, based on first principles, (=)-trans-anti-B[a]P-N2-Gua can adopt at least 16 conformations. This is a large number, and probably all are not relevant to base substitutions mutagenesis, we have used a combination of common sense and the results of our molecular mechanical calculations to conclude that three conformations are most likely to be relevant to mutagenesis. Furthermore, we noticed a correlation. In a sequence where G->T mutations predominated (5'-TGC) a base displaced conformation of (+)-trans-anti-B[a]P-N2-Gua with the dG moiety in the major groove (Gma5) was calculated to be lower in energy. In two sequences where we observed G->A mutations were found more equally (5'-CGG, 5'-GGG) Gma5 and Gmi3 were calculated to be more similar in energy. This correlation suggests the hypothesis that Gma5 is the conformation responsible for G->T mutations and Gmi3 is responsible for G->A mutations. We are pursuing this hypothesis in molecular biological/mutagenesis studies (funded separately). Herein we propose three specific aims to pursue this hypothesis using molecular modeling and computational chemical techniques.
苯并{a}芘是一种强效诱变剂/致癌物,在细胞内代谢活化,包括其(+)-抗-7,8-二醇-9,10-环氧化物[(+)-抗-B [a]PDE,产生DNA加合物,主要是N2-dG。我们发现,(+)-抗B [a]PDE能够诱导如此多样化的突变?碱基替换突变占优势,并且主要发生在G:C碱基对,其中GC->TA、GC->AT和GC->CG都是显著的(分别为57%、23%、20%)。我们已经进行了分子生物学/诱变工作,以表明(+)-trans-antiB[a]P-n2-Gus能够在5 '-TGC序列中诱导优势G->T突变(>约95%),或在5'-阿加序列中诱导优势G->A突变(->约95%)。这就提出了一个问题:一个单一的实体(即,(+)-反式-抗B[a]P-N2-Gua]根据序列背景诱导不同的突变模式?我们的工作假设是,加合物突变的复杂性是由于加合物构象的复杂性,加合物的构象,从而突变是由各种因素,特别是DNA序列的上下文控制。为了研究加合物的构象,我们进行了分子模拟,发现基于第一性原理,(=)-trans-anti-B[a]P-N2-Gua可以采用至少16种构象。这是一个很大的数字,可能都与碱基取代诱变无关,我们结合常识和分子力学计算结果得出结论,三种构象最有可能与诱变相关。此外,我们注意到一种相关性。在G->T突变占优势的序列(5 '-TGC)中,计算出在大沟(Gma 5)中具有dG部分的(+)-反式-抗B[a]P-N2-Gua的碱基置换构象能量较低。在我们观察到G->A突变的两个序列中,发现(5 '-CGG,5'-GGG)Gma 5和Gmi 3在能量上更相似。这种相关性表明了这样的假设,即Gma 5是负责G->T突变的构象,而Gmi 3是负责G->A突变的构象。我们正在分子生物学/诱变研究中追求这一假设(单独资助)。在这里,我们提出了三个具体的目标,追求这一假设使用分子建模和计算化学技术。
项目成果
期刊论文数量(15)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A hypothesis for what conformation of the major adduct of (+)-anti-B[a]PDE (N2-dG) causes G-->T versus G-->A mutations based upon a correlation between mutagenesis and molecular modeling results.
基于诱变和分子建模结果之间的相关性,假设 ( )-抗 B[a]PDE (N2-dG) 主要加合物的哪种构象会导致 G-->T 与 G-->A 突变。
- DOI:10.1093/carcin/20.1.95
- 发表时间:1999
- 期刊:
- 影响因子:4.7
- 作者:Kozack,RE;Shukla,R;Loechler,EL
- 通讯作者:Loechler,EL
Rotation about the C6-O6 bond in O6-methylguanine: the syn and anti conformers can be of similar energies in duplex DNA as estimated by molecular modeling techniques.
O6-甲基鸟嘌呤中 C6-O6 键的旋转:根据分子建模技术估计,双链体 DNA 中的顺式和反式构象异构体可能具有相似的能量。
- DOI:10.1093/carcin/12.9.1693
- 发表时间:1991
- 期刊:
- 影响因子:4.7
- 作者:Loechler,EL
- 通讯作者:Loechler,EL
Molecular modeling in mutagenesis and carcinogenesis.
诱变和癌变的分子模型。
- DOI:10.1016/0076-6879(91)03025-c
- 发表时间:1991
- 期刊:
- 影响因子:0
- 作者:Loechler,EL
- 通讯作者:Loechler,EL
How are potent bulky carcinogens able to induce such a diverse array of mutations?
强效大体积致癌物如何能够诱导如此多样化的突变?
- DOI:10.1002/mc.2940130404
- 发表时间:1995
- 期刊:
- 影响因子:4.6
- 作者:Loechler,EL
- 通讯作者:Loechler,EL
Molecular modeling of the conformational complexity of (+)-anti-B[a]PDE-adducted DNA using simulated annealing.
使用模拟退火对 ( )-抗 B[a]PDE 加合 DNA 的构象复杂性进行分子建模。
- DOI:10.1093/carcin/18.8.1585
- 发表时间:1997
- 期刊:
- 影响因子:4.7
- 作者:Kozack,RE;Loechler,EL
- 通讯作者:Loechler,EL
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
EDWARD L LOECHLER其他文献
EDWARD L LOECHLER的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('EDWARD L LOECHLER', 18)}}的其他基金
Research Conference:Mutagenesis and Carcinogenesis
研究会议:诱变与致癌
- 批准号:
6479700 - 财政年份:2002
- 资助金额:
$ 24.66万 - 项目类别:
MUTAGENIC PATHWAYS INVOLVING 5-METHYLCYTOSINE
涉及 5-甲基胞嘧啶的诱变途径
- 批准号:
6106122 - 财政年份:1997
- 资助金额:
$ 24.66万 - 项目类别:
INTERSTRAND CROSSLINKS--REPLICATION, REPAIR, MUTATIONS
链间交联——复制、修复、突变
- 批准号:
2093199 - 财政年份:1993
- 资助金额:
$ 24.66万 - 项目类别:
INTERSTRAND CROSSLINKS--REPLICATION, REPAIR, MUTATIONS
链间交联——复制、修复、突变
- 批准号:
3193201 - 财政年份:1993
- 资助金额:
$ 24.66万 - 项目类别:
INTERSTRAND CROSSLINKS--REPLICATION, REPAIR, MUTATIONS
链间交联——复制、修复、突变
- 批准号:
2093200 - 财政年份:1993
- 资助金额:
$ 24.66万 - 项目类别:
相似海外基金
TOXIC EFFECTS OF BENZOPYRENES ON IMMUNE FUNCTIONS IN AGI
苯并芘对 AGI 免疫功能的毒性作用
- 批准号:
3037954 - 财政年份:1985
- 资助金额:
$ 24.66万 - 项目类别: