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.

首席调查员/项目主任(最后、第一、中间)：马哈茂德，Taifo-2 R01 AI61528-05A1 C7N-氨基半胱醇。一类相对较新的微生物次级代谢物，具有作为治疗各种生理性疾病(如糖尿病)、传染病(如流感和艾滋病毒感染)和癌症的候选药物的巨大潜力。这是因为它们与糖类相似，糖类广泛存在于所有生物体的结构和生理系统中。在这一应用中，我们建议研究含有C7N-氨基环的天然产物的生物合成，并利用这些知识通过生物合成方法开发具有重要药学意义的先导化合物。这项研究将使用两个不同的结构模型进行：(1)在吸湿链霉菌中，C7N-氨基环醇作为天然产物的核心单元存在，以抗真菌药物validamin为代表；(2)在Nonomuraea spiralis中，C7N-氨基环醇以糖元形式存在，以抗生素吡罗米星为代表。这项研究的长期目标包括开发新的基于C7N-氨基半胱醇的药物来治疗传染病和各种生理疾病，提高产量，提供临床上重要的C7N氨基半胱醇化合物的替代生产策略，并对这类天然产物在自然界中的存在和分布提供见解。 这项应用采用了一种多学科的方法，利用分子遗传学、酶学和化学中的尖端技术来获取、利用和操纵C7N-氨基环醇生物合成基因。操纵直接参与前体形成和剪裁过程的基因将被用来创造新的生物活性化合物。这项研究包括有效霉素和吡咯米星生物合成基因簇的克隆和鉴定，以及它们的关键生物合成酶的特性。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品家族的化学多样性。