一种可利巴克丁诱导的基因毒性机制模型
Alan R Healy1,2, Herman Nikolayevskiy1, Jaymin R Patel2,3
1Department of Chemistry, Yale University , New Haven, Connecticut 06520, United States.
Journal of the American Chemical Society
|December 10, 2016
概括
合成研究显示,不和的伊米因,而不是皮里衍生物,是 colibactins 的基因毒性形式. 这些因子以及特定的结构特征对于clb+大肠杆菌强烈的DNA化至关重要.
科学领域:
- 微生物学
- 自然产品化学
- 分子生物学
背景情况:
- 胆固醇是大肠杆菌的天然产物,与DNA损伤有关.
- 负责大肠杆菌生产的 clb 基因集群存在于致病性和益生菌大肠杆菌菌株中.
- 预可菌素被认为是基因毒性可菌素的前体,但其结构和活性仍未得到证实.
研究的目的:
- 合成和评估 colibactin 衍生物以确定它们的 DNA 化活性.
- 测试 colibactins 是不和的 imines 的假设,这些 imines 通过环环开放而化 DNA.
- 阐明 colibactin 中介的 DNA 损伤的结构要求.
主要方法:
- 合成13种合成胆固醇衍生物.
- 在体外评估合成化合物的DNA结合和化活性.
- 胺和衍生物的比较分析.
主要成果:
- 不和的胺衍生物,但不含皮里的前菌素,强烈化DNA.
- 免疫,不和乳酸和环的功能对于DNA化至关重要.
- 发现一种阴离子残留物增强了DNA的化活性.
- 皮里衍生物似乎是在缺乏功能性大肠杆菌酶 (ClbP) 的情况下形成的脱路产物.
结论:
- 与 clb 基因集群相关的基因毒性是由不和的 imine colibactins 中介的,而不是含 pyridone 的 precolibactins.
- 像伊胺,不和乳酸和环等结构特征对DNA化至关重要.
- 了解导致DNA损伤的精确结构是将clb+大肠杆菌表型与特定代谢物的关键.
相关概念视频
01:25Mutagenicity and Carcinogenicity
2.1K
Mutagenicity and carcinogenicity refer to the ability of drugs to cause genetic defects and induce cancer, respectively. The International Agency for Research on Cancer (IARC) classifies agents into four groups based on their carcinogenic potential. Group 1 agents are known human carcinogens; group 2A agents are probably carcinogenic to humans; group 3 agents lack data to support their role in carcinogenesis; and group 4 includes agents for which data support that they are not likely to be...
2.1K
01:10Drugs that Destabilize Microtubules
4.2K
Microtubules are dynamic structures and can be regulated by microtubule targeting agents (MTAs). Microtubule destabilizing drugs are a class of MTAs that destabilize and prevent microtubules' polymerization. Both natural and synthetic chemicals can be found under this class of drugs. Vincristine and vinblastine, two vinca alkaloids, and colchicine were among the first to be discovered. These drugs can affect cells in various ways, either by inducing a change in cell morphology, preventing...
4.2K
01:16In-vitro Mutagenesis
17.5K
To learn more about the function of a gene, researchers can observe what happens when the gene is inactivated or “knocked out,” by creating genetically engineered knockout animals. Knockout mice have been particularly useful as models for human diseases such as cancer, Parkinson’s disease, and diabetes.
17.5K
01:30Spontaneous and Induced Mutations
2.7K
Spontaneous mutations arise infrequently during DNA replication due to errors in the process. A key factor behind these errors is tautomeric shifts in nitrogenous bases, where bases transition from keto to enol forms or amino to imino forms. This shift can alter base-pairing rules, leading to mutations. Additionally, reactive oxygen species (ROS) arising from aerobic metabolism can damage DNA, resulting in depurination (loss of a purine base) or depyrimidination (loss of a pyrimidine base).
2.7K
01:25Bioactivation and Tissue Toxicity
75
Bioactivation is a metabolic process that transforms less reactive substances into highly reactive metabolites, initiating tissue toxicity. This transformation can lead to various toxic effects, including carcinogenesis and teratogenesis. Reactive metabolites are classified into two main types: electrophiles and free radicals.Electrophiles are electron-deficient species and are produced primarily by the enzyme cytochrome P-450 during the metabolism of compounds containing carbon, nitrogen, or...
75
02:36DNA Damage can Stall the Cell Cycle
10.3K
In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
10.3K