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：
8339463
负责人：
GEORGE NEAL PHILLIPS
金额：
$ 70.52万
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/8339463
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 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）：天然产品及其衍生物在药物管道中继续发挥重要作用。随着时间的流逝，有7000种已知结构导致了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品。筛选新天然产品及其类似物将继续进行，并通过代谢工程，合成生物学以及对它们产生它们的化合物和酶的结构分析等现代方法的增强。例如，正在围绕工程系统（例如模块化聚酮化合物合成酶）建立新的生物合成路线，以产生新的化合物。还可以探索大量新的微生物天然产物，这是基因组测序数据的证明。尽管如此，新化合物的发现仍然是一项不定的努力。基因组挖掘工作以识别有趣的簇，并预测这些基因簇可能来自这些天然产物，从而开始产生假设。但是，酶与已知酶的同源性通常很低。我们建议在PSI生物学网络框架内建立一种新的伙伴关系，称为天然产品伙伴关系，以在识别新的天然产品途径的识别以及随后发现新的基于天然产品的药物的新型药物方面发挥着强大的关节作用，通过揭示新的酶的结构和活跃位点，从而通过对基因产物进行定制的特定机会，从而揭示新的结构和活跃场所，从而确定酶促产品的特定机会，从而识别酶促的机会，从而揭示新的基于天然产品的作用。和/或鉴定具有所需酶特性的新型蛋白质或结构域。 PSI网络中心与其高通量结构确定能力和通过天然产品合作伙伴关系的生物学驱动的天然产品科学家团队的组合非常有效，可以创建高影响力计划。在PSI计划中，具有PSI活动的结构生物学家的经验及其在开发技术和基础设施方面的领导能力将使向PSI生物学活动的平稳过渡。