Enzyme Discovery for Natural Product Biosynthesis

天然产物生物合成的酶发现

基本信息

批准号：
8616735
负责人：
GEORGE NEAL PHILLIPS
金额：
$ 67.53万
依托单位：
RICE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8616735
关键词：
Active Sites Amino Acids Aminoglycosides Anabolism Anti-Infective Agents Biochemical Biochemical Reaction Bioinformatics Biological Biological Factors Biological Process Biology Budgets Catalysis Cells Cephalosporins Code Data Databases Engineering Enzymes Family Funding Gene Cluster Gene Duplication Genome Genomics Goals Hand Homologous Gene Joints Knowledge Leadership Methods Microbe Mining Modeling Modern Medicine Names National Institute of General Medical Sciences Organism Pathway interactions Penicillins Pharmaceutical Preparations Pharmacologic Substance Play Positioning Attribute Principal Investigator Property Protein Structure Initiative Proteins Reaction Research Research Infrastructure Research Personnel Roentgen Rays Role Route Scientist Source Specific qualifier value Specificity Structural Biologist Structure Substrate Specificity System Technology Tetracyclines Thermodynamics Time Work Zinostatin analog base biophysical techniques design drug candidate drug discovery enzyme structure experience glycosylation glycosyltransferase improved interest knowledge base metabolic engineering microbial microorganism novel polyketide synthase programs public health relevance research study screening synthetic biology tool

项目摘要

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.

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 种已知结构催生了 20 多种商业药物，过去十年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、合成生物学以及化合物和产生它们的酶的结构分析等现代方法得到加强。例如，正在围绕工程系统（例如模块化聚酮合酶）构建新的生物合成路线，以生产新化合物。正如即将出现的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。尽管如此，新化合物的发现仍然是一项偶然的努力。基因组挖掘工作旨在识别有趣的基因簇并预测这些基因簇可能产生哪些天然产物，这些努力开始产生假设；然而，这些酶与已知酶的同源性通常较低。我们建议在 PSI 生物网络框架内创建一个名为“天然产物合作伙伴”的新合作伙伴关系，通过揭示天然产物的结构和结构，在识别新的天然产物途径以及随后发现新的基于天然产物的药物方面发挥强有力的联合作用。新型酶的活性位点，表征基因产物的酶促反应，鉴定新的天然产物，从而提供通过改变特异性和/或鉴定具有所需酶性质的新型蛋白质或结构域来鉴定和定制途径的机会。 PSI 网络中心及其高通量结构测定能力和通过天然产品合作伙伴关系由生物学驱动的天然产品科学家团队相结合，在创建高影响力计划方面处于有利地位。结构生物学家在 PSI 活动中的经验以及他们在 PSI 计划中开发技术和基础设施方面的领导力将使顺利过渡到 PSI 生物学活动成为可能。