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（Lutzomyia longipalpis）叮咬传播给人类的热带疾病，如果不治疗则是致命的，并且是世界上仅次于疟疾的第二大寄生虫杀手，每年导致20，000 - 40，000人死亡。Sobralene是最近发现的由白蛉种群产生的性聚集信息素。Sobralene有可能用于信息素引诱剂陷阱作为一种媒介控制措施。然而，索布拉烯只能以非常小的量从白蛉中分离出来，因此需要开发用于其大规模生产的方法。开发更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。这种方法已成功地应用于生产密切相关的分子，如紫杉二烯，但其应用到生产sobralene尚未探索。该项目将侧重于使用计算方法来设计和工程化一种酶，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sobralene和紫杉二烯之间的密切合成关系为指导，紫杉二烯是抗癌药物紫杉醇的生物合成替代品，紫杉醇与sobralene共同从白蛉中分离出来。这表明sobralene合酶将类似于紫杉二烯合酶，为计算研究提供了一个起点。该项目将利用密度泛函理论（DFT）等现代量子化学方法探索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.