Deciphering the steps of prodiginine biosynthesis

破译原地吉宁生物合成步骤

• 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
• 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

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）：Prodiginines 是由放线菌和其他真细菌产生的线性和环状低聚吡咯红色素抗生素家族。这类抗生素的成员因其广泛的抗真菌、抗菌活性而为人所知已有一段时间了。近年来，人们对这些天然产品产生了极大的兴趣，因为它们似乎具有显着的抗疟疾、抗癌和免疫抑制活性。我们使用一系列遗传和生化实验揭示了天蓝色链霉菌基因组中的 23 个红色基因簇编码了一条引人入胜且不寻常的途径，导致十一烷基前地精氨酸和环化衍生物链霉素 B 的形成。该过程的初始阶段涉及与脂肪酸生物合成的复杂界面，将在具体目标 1 中进一步研究。 这些阶段涉及许多具有不寻常结构和催化活性的多功能和单功能蛋白质，具体目标 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喂入适当的阻断突变体，或创建混合生物合成途径（将红色蛋白与催化活性相似但底物特异性不同的蛋白质交换），在天蓝色链球菌中产生新型环状和线性prodiginine类似物。具体目标 5 将在这些成功的基础上产生额外的新型 prodiginine 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活性。一系列化学、遗传和生物化学方法将用于这 5 个具体目标，这些目标解决了我们的长期目标：a）建立对 prodiginine 生物合成途径的酶学的全面理解，b）利用这些知识生成新颖的线性和环状 prodiginine 结构，以在人类健康中潜在应用。外行语言描述。一些细菌产生鲜红色素（prodiginines），这在许多人类健康应用中显示出前景，包括癌症治疗、对抗疟疾和其他传染病以及帮助器官移植患者。这项工作将确定这些细菌是如何产生这些原菌的，并利用这些知识来生成和鉴定具有正确化学性质和生物活性的新原菌，以用于可能的临床开发。