Deciphering the steps of prodiginine biosynthesis

破译原地吉宁生物合成步骤

基本信息

批准号：
7634480
负责人：
KEVIN A REYNOLDS
金额：
$ 38.31万
依托单位：
PORTLAND STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7634480
关键词：
Actinobacteria class Actinomyces Address Anabolism Anti-Bacterial Agents Antibiotics Antifungal Agents Antimalarials Architecture Bacteria Biochemical Biological Biological Assay Biological Factors Clinical Communicable Diseases Complex Coupled Cyclization Data Development Enzymatic Biochemistry Enzymes Eubacterium Family Fatty Acids Funding Genes Genetic Genome Glycine Health Human Hybrids Immunosuppressive Agents Knowledge Language Lauric Acids Link Malaria Metabolism Organ Transplantation Pathway interactions Phase Physical condensation Pigments Process Production Proteins Pyridoxal Phosphate Research Role Series Serine Staging Streptomyces coelicolor Structure Substrate Specificity Time Transplant Recipients Universities Work analog cancer therapy chemical genetics chemical property fascinate fatty acid biosynthesis feeding fighting gene replacement health application improved interest member mutant novel oncology oxidation prodiginine research study restoration success

项目摘要

DESCRIPTION (provided by applicant): Prodiginines are a family of linear and cyclic oligopyrrole red-pigmented antibiotics produced by actinomycetes and other eubacteria. Members of this class of antibiotics have been known for some time, as have their broad antifungal, antibacterial activity. There has been a dramatic interest in recent years in these natural products as they appear to have pronounced antimalarial, anticancer and immunosuppressant activity. We have used a series of genetic and biochemical experiments to reveal that a cluster of 23 red genes in Streptomyces coelicolor genome encode a fascinating and unusual pathway leading to formation of undecylprodiginine and a cyclized derivative, streptorubin B. The initial stages of this process involve a complex interface with fatty acid biosynthesis which will be further investigated in specific aim 1. Subsequent stages involve numerous multifunctional and monofunctional proteins with unusual architecture and catalytic activities and specific aims 2-4 will be a continuation of our studies on these. Our preliminary work has also demonstrated that we can generate novel cyclic and linear prodiginine analogues in S. coelicolor by either feeding analogues of pathway intermediates to the appropriate blocked mutants, or creation of hybrid biosynthetic pathways (exchanging Red proteins with proteins of similar catalytic activity but different substrate specificities). Specific aim 5 will build on these successes generating additional novel prodiginine structures and evaluating their biological activity in antimalarial, immunosuppressant, anticancer and antifungal assays. A wide array of chemical, genetic and biochemical approaches will be used for these 5 specific aims which address our long term objective of a) building a comprehensive understanding of the enzymology of prodiginine biosynthetic pathways and b) using this knowledge to generate novel linear and cyclic prodiginines structures for potential application in human health. Lay Language Description. Some bacteria produce bright red pigments (prodiginines) which show promise for numerous human health applications including cancer treatment, fighting malaria and other infectious diseases, and helping organ transplant patients. This work will identify how these prodiginines are made by the bacteria and use this knowledge to generate and identify new prodiginines with the correct chemical properties and biological activities for possible clinical development.

描述（由申请人提供）：天赋是一个线性和循环寡吡咯的家族，由放线菌和其他eubacteria产生的抗生素。这类抗生素的成员已有一段时间了，其广泛的抗真菌抗菌活性。近年来，这些天然产物的兴趣引起了人们的兴趣，因为它们似乎具有抗疟疾，抗癌和免疫抑制活性。我们已经使用了一系列遗传和生化实验来表明，链霉菌中的23个红色基因群簇编码了一种引人入胜且不寻常的途径，导致形成异常的素质和衍生化衍生物的链球菌。阶段涉及许多具有异常结构和催化活性的多功能和单功能蛋白，而特定的目标2-4将是我们对这些研究的延续。我们的初步工作还表明，我们可以通过将途径中间体的类似物的类似物喂入适当的封闭突变体，或者创建混合生物合成途径（将红色蛋白质与类似催化剂特异性的蛋白质交换，但具有不同的底层蛋白质）。具体目标5将基于这些成功，从而产生其他新型的杂质结构，并评估其在抗疟疾，免疫抑制剂，抗癌和抗真菌测定中的生物学活性。这5个特定目的将使用各种化学，遗传和生化方法，这些目标将解决我们的长期目标a）建立对质氨酸生物合成途径的酶学的全面理解，b）使用这些知识来生成新颖的线性和环状质质质质结构，以在人类健康中进行潜在应用。外行语言描述。一些细菌会产生鲜红色的色素（杂质），这对包括癌症治疗，抗击疟疾和其他传染病以及帮助器官移植患者的众多人类健康应用有望。这项工作将确定细菌是如何产生这些质量的，并利用这些知识来生成和识别具有正确的化学特性和生物学活性的新质量，以实现可能的临床发育。