コリバクチン誘発性遺伝子毒性のメカニズムモデル
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
まとめ
合成研究により,ピリドンの派生物ではなく,不飽和イミンがコリバクチンの遺伝子毒性形態であることを明らかにした. これらのイミンは,特定の構造的特徴とともに,clb+ E. coliによる強力なDNAアルキル化に不可欠である.
科学分野:
- 微生物学
- 自然製品化学
- 分子生物学
背景:
- コリバクチンは,DNA損傷に関連した大腸菌の天然産物です.
- コリバクチンの産生を担う clb 遺伝子クラスターは,病原性およびプロバイオティックな E. coli 菌株の両方に存在します.
- プレコリバクチンは遺伝子毒性コロリバクチンの前駆体として提案されているが,その構造と活性はまだ確認されていない.
研究 の 目的:
- コリバクチンの誘導体を合成し,そのDNAアルキル化活性を測定する.
- コリバクチンが不飽和イミンで, DNA をサイクロプロパン環開口でアルキル化するという仮説を検証する.
- コリバクチン媒介によるDNA損傷の構造的要件を解明する.
主な方法:
- 13の合成コリバクチン誘導体の合成
- 合成された化合物のDNA結合とアルキル化活動のインビトロ評価.
- イミンとピリドンの誘導体の比較分析
主要な成果:
- 飽和していないイミン誘導体だが,ピリドンを含まないプレコリバクチンは,強力にDNAをアルキル化する.
- イミン,不飽和ラクトーム,サイクロプロパン機能はDNAアルキル化に不可欠である.
- カチオンの残留はDNAのアルキル化活性を増強することが判明した.
- ピリドンの誘導体は,機能的なコリバクチンペプチダゼ (ClbP) が存在しない状態で形成される経路外産物である.
結論:
- clb遺伝子クラスターに関連した遺伝子毒性は,ピリドンを含むプレコリバクチンではなく,不飽和イミンコリバクチンによって媒介されます.
- イミン,不飽和ラクトーム,サイクロプロパンなどの構造的特徴はDNAアルキル化に不可欠です.
- clb+E. coliのフェノタイプを特定の代謝産物と結びつけるには,DNA損傷に起因する正確な構造を理解することが重要です.
関連する概念動画
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