合规锁定非共价网络 在As的功能模型中调节甲基化(III) SAM甲基转移酶
Rudra Shankar Pati1, Amirul Islam1, Aravindh Raj Kannan1
1Department of Chemistry, Indian Institute of Technology Tirupati, Tirupati, AP 517619, India.
Inorganic chemistry
|November 3, 2025
概括
非共价相互作用是甲基化效率的关键. 新的 thioimidazolium 剂模仿酶,改进的设计显示高达 80 倍的速率增加和近乎完美的效率用于排毒.
科学领域:
- 生物化学 生物化学
- 有机化学 有机化学
- 催化剂是一种催化剂.
背景情况:
- 非共价相互作用对酶催化非常重要,影响键激活和过渡状态稳定.
- 酸盐S-adenosylmethionine甲基转移酶 (ArsM) 通过酸盐生物甲基化对于毒解毒至关重要,但其效率尚未完全理解.
- 了解这些相互作用可以导致改进合成甲基化剂.
研究的目的:
- 阐明非共价相互作用在调节甲基化效率中的作用.
- 设计基于胺的新型甲基化剂,以模拟酶过程.
- 建立非共价相互作用和甲基化率之间的结构功能关系.
主要方法:
- 对SAM和As-bound ArsM进行分子动力学 (MD) 模拟,以确定关键的稳定残留物 (Gly91,Tyr70).
- 基于 thioimidazolium 的甲基化剂 (1-7) 的设计和合成,具有量身定制的分子内相互作用.
- 对设计剂与酶过程的甲基化率和效率进行比较分析.
主要成果:
- MD模拟显示了ArsM.中的保存残留物稳定非共价相互作用.
- 双 (4) 和四硫胺 (7) 衍生物显示显著的速率提升 (高达80倍) 和高效率 (98%的7对比16%的1).
- 在代理7中具有合作性非共价相互作用的符合锁定框架显著改善了甲基化.
- 代理7的硫中心促进了电子移位,降低了激活障碍,并实现了完整的生物模拟甲基化循环.
结论:
- 非共价相互作用在确定甲基化效率方面发挥着关键作用.
- 设计的 thioimidazolium 剂可以有效地模仿酶的甲基化过程.
- 这项工作为开发基于结构-功能相关性的高效合成甲基化剂提供了新的策略.
相关概念视频
Covalently Linked Protein Regulators
8.6K
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
These groups modify specific amino acids in a protein....
8.6K
Phase II Reactions: Methylation Reactions
665
Methylation is a phase II biotransformation process involving the attachment of a methyl group to a substrate. Enzymes known as methyltransferases orchestrate this reaction.
The mechanism of methylation unfolds in two stages. The first stage sees a methyltransferase enzyme facilitating the transfer of a methyl group from S-adenosylmethionine (SAM) to the substrate, forming S-adenosylhomocysteine (SAH). The second stage involves further metabolism of SAH into homocysteine, which can be recycled...
The mechanism of methylation unfolds in two stages. The first stage sees a methyltransferase enzyme facilitating the transfer of a methyl group from S-adenosylmethionine (SAM) to the substrate, forming S-adenosylhomocysteine (SAH). The second stage involves further metabolism of SAH into homocysteine, which can be recycled...
665
Cooperative Binding of Transcription Regulators
7.1K
Transcriptional regulators bind to specific cis-regulatory sequences in the DNA to regulate gene transcription. These cis-regulatory sequences are very short, usually less than ten nucleotide pairs in length. The short length means that there is a high probability of the exact same sequence randomly occurring throughout the genome. Since regulators can also bind to groups of similar sequences, this further increases the chances of random binding. Transcriptional regulators form...
7.1K
Epigenetic Regulation
3.7K
Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...
X-chromosome...
3.7K
Structural Isomerism
21.4K
Isomerism in Complexes
Isomers are different chemical species that have the same chemical formula. Structural isomerism of coordination compounds can be divided into two subcategories, the linkage isomers and coordination-sphere isomers.
Linkage isomers occur when the coordination compound contains a ligand that can bind to the transition metal center through two different atoms. For example, the CN− ligand can bind through the carbon atom or through the nitrogen atom. Similarly, SCN− can...
Isomers are different chemical species that have the same chemical formula. Structural isomerism of coordination compounds can be divided into two subcategories, the linkage isomers and coordination-sphere isomers.
Linkage isomers occur when the coordination compound contains a ligand that can bind to the transition metal center through two different atoms. For example, the CN− ligand can bind through the carbon atom or through the nitrogen atom. Similarly, SCN− can...
21.4K
Ligand Binding and Linkage
5.5K
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
5.5K


