一个机制性假设,用于阿司匹林诱导的转换在脂质媒介产生的循环氧基因酶-2的
1Department of Drug Science and Technology, Via Pietro Giuria 9, 10125 Torino, Italy. paolo.tosco@unito.it
Journal of the American Chemical Society
|June 22, 2013
概括
在前列腺素生产中的循环氧化酶-2 (COX-2) 立体特异性由硬质屏蔽决定. 亚司匹林对COX-2的乙化改变了这一点,转移了脂质介质生成,这是通过计算建模证实的.
科学领域:
- 生物化学 生物化学
- 酶学 是一种酶学.
- 分子生物学分子生物学
背景情况:
- 循环氧化原酶 (COX) 酶催化阿拉基酸的立体特定氧化,产生前列腺素.
- COX-2活性,特别是它的立体特异性和产品分布,通过像Ser530乙化这样的翻译后修饰来调节,特别是在阿司匹林治疗后.
- 在COX-2的高立体特异性和阿司匹林诱导的改变的影响背后的精确分子机制仍然不完全理解.
研究的目的:
- 在氧化反应中阐明循环氧化酶-2 (COX-2) 立体特异性的分子基础.
- 解释COX-2的阿司匹林治疗后观察到的脂质媒介产生的转变的原因.
- 提出并通过计算验证COX-2立体特异性的机械学假设.
主要方法:
- 一个机械学假设的发展,重点关注固态屏蔽作为立体特异性的决定因素.
- 创建一个计算模型来模拟COX-2氧化模式.
- 模型与本地和阿司匹林抑制的COX-2实验数据的验证.
主要成果:
- 提出的假设确定了固态屏蔽作为控制COX-2氧化立体特异性的主要因素.
- 计算模型准确地复制了原生COX-2的实验氧化模式.
- 该模型还成功地重现了在阿司匹林抑制的COX-2中观察到的改变的氧化模式.
结论:
- 绝缘屏蔽是COX-2催化氧化中观察到的高立体特异性的关键决定因素.
- 亚司匹林诱导COX-2中Ser530的乙化改变了硬质约束,导致产生的脂质介质的类型和相对数量的转变.
- 计算建模为理解酶机制和预测药物抑制等修改效应提供了强大的工具.
相关概念视频
Gastritis-II: Pathophysiology
Gastritis is marked by disruption of the mucosal barrier that usually protects the stomach tissue from digestive juices and manifests in acute and chronic forms.
In acute gastritis, the gastric mucosa becomes swollen and red and undergoes superficial erosion. Superficial ulceration may lead to bleeding.
In chronic gastritis, persistent or repeated insults lead to chronic inflammatory changes and, eventually, thinning or atrophy of the gastric tissue.
Gastritis can stem from various causes, each...
In acute gastritis, the gastric mucosa becomes swollen and red and undergoes superficial erosion. Superficial ulceration may lead to bleeding.
In chronic gastritis, persistent or repeated insults lead to chronic inflammatory changes and, eventually, thinning or atrophy of the gastric tissue.
Gastritis can stem from various causes, each...
Peptic Ulcer Disease II: Pathophysiology
Peptic ulcer disease develops when protective mechanisms of the gastrointestinal mucosa are overwhelmed by harmful factors, leading to localized erosions in the stomach or proximal duodenum. The main causes are Helicobacter pylori infection and chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs).Helicobacter pylori–Induced InjuryBacterial Adaptation and Colonization:H. pylori is a spiral, Gram-negative bacterium adapted to the acidic stomach. and transmitted through oral-oral or...
Peptic Ulcer Disease II: Pathophysiology
Peptic Ulcer Disease (PUD) is characterized by the development of ulcers in the stomach or duodenal mucosa. Its pathophysiology is complex, involving a balance between damaging and protective elements.
Damaging agents such as Helicobacter pylori, gastric acid, pepsin, and nonsteroidal anti-inflammatory drugs (NSAIDs) can weaken the mucosal defense, allowing hydrogen ions to infiltrate back and harm epithelial cells.
Damaging agents such as Helicobacter pylori, gastric acid, pepsin, and nonsteroidal anti-inflammatory drugs (NSAIDs) can weaken the mucosal defense, allowing hydrogen ions to infiltrate back and harm epithelial cells.
Drugs for Peptic Ulcer Disease: Prostaglandin Analogs as Mucosal Protective Agents
The gastric mucosa produces prostaglandins E2 (PGE2) and prostacyclin (PGI2), crucial in maintaining gastric health. They exert cytoprotective effects, including increasing bicarbonate secretion, releasing protective mucin, reducing gastric acid output, and preventing harmful vasoconstriction. These effects are mediated through various receptors, such as EP1, EP2, EP3, and EP4.
Non-steroidal anti-inflammatory drugs (NSAIDs) can induce peptic ulcers by inhibiting cyclooxygenase, decreasing...
Non-steroidal anti-inflammatory drugs (NSAIDs) can induce peptic ulcers by inhibiting cyclooxygenase, decreasing...
Acid Suppressive Drugs for Peptic Ulcer Disease: Histamine H2-Receptor Antagonists
Histamine H2 receptors, which are intricately located on the basolateral membrane of parietal cells, play a crucial role in modulating gastric acid secretion. When released from enterochromaffin-like cells, histamine engages H2 receptors, initiating the cyclic AMP (cAMP) pathway. In this pathway, adenylyl cyclase converts ATP into cAMP, elevating intracellular cAMP levels. The activation of protein kinase A follows, stimulating the proton pump. This stimulation prompts the secretion of hydrogen...
Pathophysiology of Peptic Ulcer Disease: Injurious Factors
Peptic ulcers are sores on the stomach's inner lining and the upper small intestine, which are the result of disruptions in the mucosal layer that houses parietal cells which produce gastric acid, and chief cells which secrete pepsinogen.
In the antrum region, G cells secrete the gastrin hormone that binds to gastrin-cholecystokinin-B (CCK2) receptors on parietal and enterochromaffin-like (ECL) cells in the fundic glands. Simultaneously, the vagus nerve releases acetylcholine, which binds to M3...
In the antrum region, G cells secrete the gastrin hormone that binds to gastrin-cholecystokinin-B (CCK2) receptors on parietal and enterochromaffin-like (ECL) cells in the fundic glands. Simultaneously, the vagus nerve releases acetylcholine, which binds to M3...
