EVOLUTION OF METABOLISM

新陈代谢的进化

• 批准号: 6348229
• 负责人: CHRISTIAN FORST
• 金额: $ 10.43万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6348229
• 关键词: bioengineering /biomedical engineering; biological products; biomedical resource; lipids; structural biology

The enzyme prostaglandin H2 synthase-1 (PGHS-1) catalyzes the transformation of the essential fatty acid, arachidonic acid (AA), to prostaglandin H2 [17]. Aspirin, flurbiprofen, and other non-steroidal anti-inflammatory drugs directly target PGHS-1 and inhibit the first step of its transformation by preventing access of AA to the cyclooxygenase active site. Based on the crystal structure of PGHS-1, with flurbiprofen bound at the active site, a model for AA embedded in the enzyme has been suggested, in which AA replaces the inhibitor [18]. The aim of the investigation is to elucidate the folding of AA into the narrow hydrophobic binding channel of the cyclooxygenase site, and to identify key residues guiding AA binding. Steered Molecular Dynamics calculations (SMD) [3-8, 103, 104] of enforced unbinding were carried out on one monomer (9,000 atoms) of the PGHS-1 homo-dimer with AA bound in its putative cyclooxygenation site, leading to the exit of the ligand from its narrow hydrophobic binding channel*. AA contains four rigid cis double bonds connected to each other by a pair of conformationally flexible single bonds. The unbinding mechanism can be described as a series of rotations around these single bonds that leave the "rigid backbone" of the fatty acid formed by the conformationally inflexible cis double bonds relatively unaffected. Our hypothesis is that this type of concerted motion is specific for the chemical structure of AA and is important for the binding and recognition mechanism. Another set of simulations was carried out with the Targeted Molecular Dynamics (TMD) method [105]. A comparison of the SMD and TMD simulations revealed that the pathways generated by both methods show very similar modes of concerted rotations around single bonds during the unbinding of AA.

酶前列腺素H2合酶1（PGHS-1）催化 必需脂肪酸，花生四烯酸（AA）的转化为 Prostaglandin H2 [17]。 阿司匹林，弗洛比哌芬和其他非甾体类 抗炎药直接靶向PGHS-1并抑制第一个 通过防止AA访问其转换的步骤 环氧合酶活性位点。 基于PGHS-1的晶体结构， 在活动位置结合的氟吡芬，AA嵌入的模型 已经提出了酶，其中AA取代了抑制剂 [18]。 调查的目的是阐明AA的折叠 进入环氧合酶的窄疏水结合通道 站点，并确定指导AA结合的关键残留物。 转向 强制执行的分子​​动力学计算（SMD）[3-8，103，104] 在PGHS-1的一个单体（9,000个原子）上进行未连接 与AA结合的同性二聚体在其推定的环氧位点， 导致配体从其狭窄的疏水结合出口 渠道*。 AA包含四个与每个连接的刚性顺式双键 另一个通过一对构象柔性的单键。 这 解开机制可以描述为周围的一系列旋转 这些单个键，留下脂肪酸的“刚性骨架” 由构象不灵活的顺式双键相对较大 不受影响。 我们的假设是，这种一致的运动是 特定于AA的化学结构，对于 结合和识别机制。 另一组模拟是 用靶向分子动力学（TMD）方法进行[105]。 SMD和TMD模拟的比较表明了途径 两种方法生成 AA解开期间，围绕单键旋转。