Investigating (di)terpenoid biosynthesis

天然产品无论是直接还是作为铅，都有提供相当大一部分铅的公认记录 人类药物的化合物。在天然产物中，萜类化合物(异戊二烯)最突出的是 是最大的一类(已知的50,000)，这里的目标是20碳二萜类化合物 其中很大一部分(&gt；12,000已知)。二萜类化合物的广泛多样化表明 可由该C20主链形成的多种碳氢骨架，尤指十氢 在与Labdane相关的二萜类化合物(&gt；7000已知)中发现的核心环结构，提供了有利的支架 用于生物活性的派生。事实上，许多与拉布丹相关的二萜类化合物被用作 药物(例如，抗生素多替林)或正在为这种用途进行研究(例如， 丹参酮、雷公藤甲素、穿心莲内酯等)。此外，我们还发现， 人类病原体结核分枝杆菌利用与拉布丹相关的二萜代谢 构建一种免疫调节因子。因此，我们在此建议继续我们富有成效的 产生生物活性二萜类化合物所需的生物合成酶的研究。具体地说，我们将构建 在我们以前在这一领域的工作基础上，包括对具有 提供了一系列二萜类化合物的新的生物合成途径，以及从战略上阐明 精选的二萜类代谢网络。这份米拉提案涵盖了我们在这一领域的系统研究， 推进我们的长期目标，设计生产酶和代谢途径 靶向文库和特定的单一萜类“天然”产物，它们已经被用于 药物效用调查。

Natural products have a proven record of providing a significant fraction, either directly or as lead compounds, of human medicines. Among natural products, the terpenoids (isoprenoids) stand out as being the largest class (>50,000 already known), with the 20-carbon diterpenoids targeted here forming a significant fraction of these (>12,000 known). The extensive diversification of diterpenoids indicates that the manifold hydrocarbon skeletons that can be formed from this C20 backbone, particularly the decalin core ring structure found in the labdane-related diterpenoids (>7,000 known), provide privileged scaffolds for derivation of biological activity. Indeed, a number of these labdane-related diterpenoids are used as pharmaceuticals (e.g., the antibiotic mutilins) or are being investigated for such use (e.g., the tanshinones, triptolide, andrographolide, etc.). In addition, we have contributed to the discovery that the human pathogen Mycobacterium tuberculosis utilizes labdane-related diterpenoid metabolism in construction of an immune-modulatory factor. Accordingly, we propose here to continue our productive studies of the biosynthetic enzymes required to produce bioactive diterpenoids. Specifically, we will build on our previous work in this area, which includes investigations of enzymatic structure-function that have provided novel biosynthetic access to an array of diterpenoids, as well as elucidation of strategically selected diterpenoid metabolic networks. This MIRA proposal covers our systematic studies in this area, advancing our long-term goal of engineering enzymes and metabolic pathways for the production of targeted libraries and specific individual terpenoid ‘natural’ products, which are being already using for investigation of pharmaceutical utility.