Biosynthesis Approach to Novel Bioactive Aminocyclitols

新型生物活性氨基环醇的生物合成方法

• 批准号: 7662986
• 负责人: TAIFO MAHMUD
• 金额: $ 29.24万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7662986
• 关键词: Acarbose; Actinobacteria class; Actinomyces; Adverse effects; Anabolism; Animals; Antibiotics; Antidiabetic Drugs; Antifungal Agents; Antifungal Antibiotics; Autoimmune Diseases; Bacteria; Basen; Biochemistry; Biodiversity; Biological; Biological Factors; Chemicals; Chemistry; Cloning; Communicable Diseases; Data; Development; Diabetes Mellitus; Disease; Enzymatic Biochemistry; Enzymes; Family; Funding; Gene Cluster; Genes; Genetic; Goals; HIV Infections; Human; Hydrolase; Influenza; Intestines; Investigation; Knowledge; Life; Malignant Neoplasms; Methods; Modeling; Molecular Genetics; Multi-Drug Resistance; Nature; Order Coleoptera; Organism; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Principal Investigator; Process; Production; Proteins; Research; Rosa; Soil; Streptomyces; System; Technology; Time; Virus; Work; analog; antitumor agent; base; combat; drug candidate; drug discovery; improved; infectious disease treatment; insight; interdisciplinary approach; microbial; microorganism; novel; programs; success; sugar; trestatin; validamycin A; validamycins; voglibose

Principal Investigator/Program Director (Last, first, middle): Mahmud, Taifo - 2 R01 AI61528-05A1 The C7N-aminocyclitols. a relatively new class of microbial secondary metabolites, have great potential to be developed as drug candidates for the treatment of various physiological disorders (e.g., diabetes), infectious diseases (e.g., influenza and HIV infections), and cancer. This is due to their resemblance to sugar moieties, which are widely involved in structural and physiological systems in all living organisms. In this application, we propose to study the biosynthesis of C7N-aminocyclitolcontaining natural products and to use the knowledge to develop pharmaceutically important leads via biosynthetic approaches. The study will be carried out using two structurally distinct models: (1) the C7N aminocyclitols present as a core unit of natural products, represented by the antifungal agent validamycin, in S. hygroscopicus; and (2) the C7N-aminocyclitols present as a glycon, represented by the antibiotic pyralomicin, in Nonomuraea spiralis. The long-term objectives of this study include developing new C7N-aminocyclitol-based drugs to treat infectious diseases and various physiological disorders, improving production yields and providing alternative production strategies of clinically important C7Naminocyclitol compounds, and providing insights about the occurrence and distribution of this class of natural products in nature. This application employs a multidisciplinary approach that utilizes cutting-edge technologies in molecular genetics, enzymology, and chemistry to access, utilize and manipulate C7N-aminocyclitol biosynthetic genes. Manipulation of genes directly involved in precursor formation and tailoring process will be used to create novel biologically active compounds. The study includes the cloning and elucidation of the biosynthetic gene clusters of validamycin and pyralomicin; and characterization of their key biosynthetic enzymes. The knowledge and methods that arise from these studies will also be widely applicable to expanding the chemical diversity of other families of bioactive natural products.

首席研究员/计划总监（最后，第一，中间）：塔福 - 2 R01 AI61528-05A1 C7N-氨基细胞素醇。一类相对较新的微生物二级代谢产物具有巨大的潜力，可以作为候选药物来治疗各种生理疾病（例如糖尿病），传染病（例如流感和艾滋病毒感染）和癌症。这是由于它们与糖部分的相似之处，这些糖部分广泛参与了所有生物体的结构和生理系统。在此应用中，我们建议研究C7N-氨基醇二醇的天然产物的生物合成，并利用知识通过生物合成方法来开发具有药物重要的铅。这项研究将使用两个结构上不同的模型进行：（1）C7N氨基辛醇作为天然产物的核心单位，以抗真菌剂验证毒素为代表，在Hygroscopicus中； （2）在Nonomuraea spiralis中以抗生素吡拉姆细胞素为代表的C7N-氨基细胞素醇表示为糖。这项研究的长期目标包括开发新的C7N-氨基细胞素的药物来治疗传染病和各种生理疾病，提高产量，并提供临床上重要的C7型C7型C7型C7型C7型C7型C7型C7型C7型C7型C7型C7型neminoinocyclitol化合物，并提供有关自然产物中这种天然产物的出现和分布的见解。 该应用采用了一种多学科方法，该方法利用了分子遗传学，酶学和化学方面的尖端技术来访问，利用和操纵C7N-氨基核细胞素的生物合成基因。对直接参与前体形成和裁缝过程的基因操纵将用于创建新型的生物活性化合物。该研究包括有效氨基霉素和吡拉姆米辛的生物合成基因簇的克隆和阐明；以及其关键生物合成酶的表征。这些研究产生的知识和方法也将广泛适用于扩大其他生物活性天然产物家庭的化学多样性。