Enzyme Discovery for Natural Product Biosynthesis

描述（由申请人提供）：天然产物及其衍生物继续在药物管道中发挥重要作用。随着时间的推移，7000种已知的结构已经产生了20多种商业药物，过去十年中批准的新药中约有一半是基于天然产物。新的天然产物及其类似物的筛选将继续进行，并通过代谢工程、合成生物学、化合物结构分析和产生它们的酶等现代方法得到加强。例如，新的生物合成路线正在围绕模块化聚酮合成酶等工程系统建立，以产生新的化合物。正如基因组测序数据所证明的那样，仍有大量新的微生物天然产物有待探索。然而，新化合物的发现仍然是一项偶然的努力。基因组挖掘工作，以确定有趣的集群和预测自然产物可能来自这些基因集群开始产生假设；然而，这些酶与已知酶的同源性通常很低。我们建议在PSI生物网络框架内建立一个新的合作伙伴关系，命名为天然产物合作伙伴关系，通过揭示新酶的结构和活性位点，表征基因产物的酶促反应，在鉴定新的天然产物途径和随后发现新的天然产物药物方面发挥强大的共同作用。鉴定新的天然产物，从而通过改变特异性和/或鉴定具有所需酶性质的新蛋白质或结构域，提供鉴定和定制途径的机会。具有高通量结构测定能力的PSI网络中心与通过天然产品合作伙伴关系的天然产品科学家的生物学驱动团队的结合，强有力地定位于创建一个高影响力的计划。结构生物学家在PSI活动中的经验以及他们在PSI项目中开发技术和基础设施方面的领导地位将使PSI生物学活动的顺利过渡成为可能。

DESCRIPTION (provided by applicant): Natural products and their derivatives continue to play an important role in the drug pipeline. Over time, 7000 known structures have led to more than 20 commercial drugs, and about half of the new drugs approved in the last decade are based on natural products. Screening of new natural products and their analogs will continue, and be enhanced by modern methods such as metabolic engineering, synthetic biology, and structural analysis of compounds and the enzymes that produce them. For example, new biosynthetic routes are being built around engineered systems such as the modular polyketide synthases to produce new compounds. There are also still a tremendous number of new microbial natural products to be explored, as evidenced by the genomic sequencing data coming forth. Nevertheless, the discovery of new compounds remains an adventitious endeavor. Genome mining efforts to identify interesting clusters and to predict what natural products might come from these clusters of genes are beginning to produce hypotheses; however the homology of the enzymes to known enzymes is generally low. We propose to create a new partnership, named the Natural Products Partnership, within the PSI Biology Network framework to play strong joint roles in both the identification of new natural product pathways and the subsequent discovery of new natural product-based pharmaceuticals by revealing the structures and active sites of novel enzymes, characterizing the enzymatic reactions of the gene products, identifying new natural products and thus offering opportunities to identify and customize the pathways by altering specificities and/or identifying novel proteins or domains with desired enzymatic properties. The combination of the PSI Network Centers with their high-throughput structure determination capability and the biology-driven team of natural products scientists through the Natural Products Partnership are strongly positioned to create a high impact program. The experience of the structural biologists with PSI activities and their leadership in developing technologies and infrastructure in the PSI program will make a smooth transition to PSI Biology activities possible.