Deciphering the steps of prodiginine biosynthesis

破译原地吉宁生物合成步骤

• 批准号: 7414458
• 负责人: KEVIN A REYNOLDS
• 金额: $ 37.13万
• 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/7414458
• 关键词: Actinobacteria class; Actinomyces; Address; Anabolism; Anti-Bacterial Agents; Antibiotics; Antifungal Agents; Antimalarials; Architecture; Bacteria; Biochemical; Biochemical Genetics; Biological; Biological Assay; Biological Factors; Class; 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是一类由放线菌和其他真细菌产生的线性和环状低聚吡咯红色抗生素。这类抗生素的成员已经知道了一段时间，因为它们具有广泛的抗真菌、抗菌活性。近年来，人们对这些天然产物产生了极大的兴趣，因为它们似乎具有明显的抗疟疾、抗癌和免疫抑制活性。我们通过一系列的遗传和生化实验发现，在蓝彩色链霉菌基因组中，有23个红色基因组成的一簇编码了一条迷人而不寻常的途径，导致了11基子氨酸和环化衍生物链torubin b的形成。这一过程的初始阶段涉及到脂肪酸生物合成的复杂界面，这将在特定目的1中进一步研究。随后的阶段涉及许多具有不同寻常结构和催化活性的多功能和单功能蛋白质和特定目标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给适当的阻断突变体，或创建杂交生物合成途径（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S. coelicolor中产生新的环状和线性的prodigine类似物。具体目标5将在这些成功的基础上产生更多新的浪子氨酸结构，并评估其在抗疟疾、免疫抑制、抗癌和抗真菌检测中的生物活性。广泛的化学、遗传和生化方法将用于这5个具体目标，以解决我们的长期目标：A)建立对子浪子碱生物合成途径的酶学的全面理解；b)利用这些知识生成新的线性和循环的子浪子碱结构，以用于人类健康的潜在应用。外行语言描述。一些细菌会产生亮红色的色素（浪子碱），这种色素在许多人类健康方面都有应用前景，包括治疗癌症、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浪子的，并利用这些知识来产生和识别具有正确化学性质和生物活性的新浪子，以用于可能的临床开发。