Computational Engineering of the Biosynthesis of the Sand Fly Pheromone Sobralene

内脏利什曼病(VL)是一种通过雌性沙蝇叮咬传播给人类的热带疾病，如不治疗可致命，是仅次于疟疾的世界第二大寄生虫杀手，每年导致20,000-40,000人死亡。Sobralene是最近发现的一种由沙蝇种群产生的性聚集信息素。Sobralene具有作为媒介控制措施用于信息素引诱剂诱捕的潜力。然而，从沙蝇中只能分离出极少量的长春花烯，因此需要开发方法来实现其大规模生产。发展大规模生产的一种方法是利用酶来执行化学合成中的关键步骤。这种方法已经成功地应用于紫杉烯等密切相关分子的生产，但还没有人探索它在紫杉烯生产中的应用。该项目将侧重于利用计算方法为一种酶的设计和工程提供信息，该酶可以催化从香叶基香叶基焦磷酸(GGPP)合成Sobralene。这项工作将以长春花烯和紫杉二烯之间的密切合成关系为指导，紫杉烯是抗癌药物紫杉醇的生物合成前驱，紫杉醇是从沙蝇中与长春花烯共同分离出来的。这表明Sobralene合成酶将类似于紫杉二烯合成酶，为计算研究提供了一个起点。该项目将使用密度泛函理论(DFT)等现代量子化学方法来探索GGPP转化为Sobralene的反应路径和过渡态。该项目的一个关键组成部分是了解酶环境如何影响反应路径。该项目与最初提交的项目没有任何变化。

Visceral leishmaniasis (VL) is a tropical disease transmitted to humans through the bite of the female sand fly (Lutzomyia longipalpis) which is fatal if untreated and is the second largest parasite killer in the world, after malaria resulting in 20,000-40,000 fatalities per year. Sobralene is a recently discovered sex-aggregation pheromone produced by populations of the sand fly. Sobralene has the potential to be used in pheromone attractant traps as a vector control measure. However, sobralene can only be isolated in very small quantities from the sand flies, and consequently methods need to be developed for its larger scale production. One approach to develop larger scale production is to exploit enzymes to perform key steps in the chemical synthesis. This approach has been successfully applied to the production of closely related molecules such as taxadiene, but its application to the production of sobralene has not been explored. This project will focus on the use of computational methods to inform the design and engineering of an enzyme that can catalyse the synthesis of sobralene from geranyl geranyl pyrophosphate (GGPP). The work will be guided by the close synthetic relationship between sobralene and taxadiene a biosynthetic precurser to the anti-cancer drug Taxol which was co-isolated with sobralene from the sand flies. This suggests that the sobralene synthase will be similar to the taxadiene synthase, providing a starting point for the computational studies. The project will use modern quantum chemical methods such as density functional theory (DFT) to explore the reaction path and transition states for the conversion of GGPP to sobralene. A key component of the project is to understand how the enzyme environment affects the reaction path. The project has no changed from the one originally submitted.