Anti-Tumor Mechanism of the Monoterpens

单萜的抗肿瘤机制

• 批准号: 6740900
• 负责人: HEE-WON PARK
• 金额: $ 22.5万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6740900
• 关键词: X ray crystallography; active sites; alkyltransferase; antineoplastics; biological products; catalyst; chemical binding; chemical structure; computer simulation; electrospray ionization mass spectrometry; enzyme inhibitors; enzyme structure; enzyme substrate complex; guanine nucleotide binding protein; mass spectrometry; mitogen activated protein kinase; molecular dynamics; monoterpenes; phosphorylation; site directed mutagenesis

DESCRIPTION (provided by applicant): Limonene and perillyl alcohol are monoterpenes that are dietary components as well as food flavoring agents and scent additives. Limonene is abundant in orange peel oil, and perillyl alcohol in cherry and spearmint. These compounds have shown potential as natural anti-cancer agents. The monoterpenes have been proposed to inhibit oncogenic protein prenylation by blocking the activity of both farnesyltransferase (FTase) and geranylgeranyltransferase type I (GGTase-I). Combination treatment with synthetic inhibitors of FTase and GGTase-I has been pursued as an avenue of cancer therapy, but many of available GGTase-I inhibitors are excessively toxic. The monoterpenes are naturally occurring, nontoxic inhibitors of both prenyltransferases. These studies seek to elucidate the structural basis of this dual inhibitory effect of the monoterpenes. The working hypothesis of this proposal is that the monoterpenes interfere with substrate binding to FTase and GGTase-I by occupying the similar hydrophobic binding pockets of the prenyltransferases. A combination of x-ray crystallography, mass spectrometry, and biochemical analysis will be used to complete two specific aims: 1. Determine the structural changes of FTase and GGTase-I that are induced by phosphorylation and establish how phosphorylation regulates prenylation activity 2. Define the mechanism by which the monoterpenes inhibit FTase/GGTase-I prenylation activity These findings will provide a structural basis for understanding how the monoterpenes suppress tumors via FTase/GGTase-I inhibition. The monoterpene-bound structures of these prenyltransferases will also advance the design of compounds that are more effective than the monoterpenes but less toxic than the existing synthetic inhibitors. Such dual inhibitors of FTase and GGTase-I would be useful for treatment of various human malignancies.

描述（由申请人提供）：柠檬烯和紫苏醇是单萜烯，是膳食成分以及食品调味剂和香味添加剂。橙皮油中富含柠檬烯，樱桃和留兰香中富含紫苏醇。这些化合物已显示出作为天然抗癌剂的潜力。已提出单萜通过阻断法呢基转移酶 (FTase) 和香叶基香叶基转移酶 I 型 (GGTase-I) 的活性来抑制致癌蛋白异戊二烯化。 FTase 和 GGTase-I 合成抑制剂的联合治疗一直被视为癌症治疗的一种途径，但许多可用的 GGTase-I 抑制剂毒性过高。单萜是两种异戊烯基转移酶的天然无毒抑制剂。这些研究试图阐明单萜的这种双重抑制作用的结构基础。 该提议的工作假设是单萜通过占据异戊二烯基转移酶的相似疏水性结合袋来干扰底物与 FTase 和 GGTase-I 的结合。 X 射线晶体学、质谱和生化分析的结合将用于完成两个具体目标： 1. 确定磷酸化诱导的 FTase 和 GGTase-I 的结构变化，并确定磷酸化如何调节异戊二烯化活性 2. 明确单萜抑制 FTase/GGTase-I 异戊二烯化活性的机制 这些发现将为理解单萜如何通过 FTase/GGTase-I 抑制来抑制肿瘤提供结构基础。这些异戊烯基转移酶的单萜结合结构也将促进比单萜更有效但比现有合成抑制剂毒性更低的化合物的设计。这种FTase和GGTase-I的双重抑制剂可用于治疗各种人类恶性肿瘤。