Enzyme Discovery for Natural Product Biosynthesis

描述(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种已知结构导致了20多种商业药物，在过去十年中批准的新药中，约有一半是基于天然产品。对新的天然产物及其类似物的筛选将继续进行，并将通过代谢工程、合成生物学和化合物及其产生的酶的结构分析等现代方法加强。例如，围绕模块化聚酮合成酶等工程系统正在建立新的生物合成路线，以生产新的化合物。基因组测序数据的出现证明，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。为了识别有趣的基因簇并预测这些基因簇可能产生什么天然产物的基因组挖掘工作开始产生假说；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伙伴关系，称为天然产品伙伴关系，通过揭示新的酶的结构和活性部位，表征基因产物的酶反应，识别新的天然产品，从而通过改变特异性和/或识别具有所需酶性质的新的蛋白质或结构域，在识别新的天然产物途径和随后发现新的基于天然产物的药物方面发挥强大的联合作用。PSI网络中心凭借其高通量结构确定能力，以及通过天然产品合作伙伴关系由生物驱动的天然产品科学家团队的结合，为创建高影响力的项目奠定了坚实的基础。具有PSI活动的结构生物学家的经验，以及他们在PSI计划中开发技术和基础设施方面的领导能力，将使PSI生物学活动的平稳过渡成为可能。

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.