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: 7847637
• 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 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7847637
• 关键词: Acarbose; Actinobacteria class; Actinomyces; Adverse effects; Anabolism; Animals; Antibiotics; Antidiabetic Drugs; Antifungal Agents; Antifungal Antibiotics; Autoimmune Diseases; Bacteria; Biochemistry; Biodiversity; Biological; Biological Factors; Chemicals; Chemistry; Cloning; Communicable Diseases; Coupled; Data; Diabetes Mellitus; Disease; Enzymatic Biochemistry; Enzymes; Escherichia coli; Family; Funding; Gene Cluster; Genes; Genetic; 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; Pseudomonas; Research; Rosa; Soil; Streptomyces; System; Technology; Time; Work; analog; antitumor agent; base; chemical synthesis; combat; drug candidate; drug discovery; fungus; improved; insight; interdisciplinary approach; microbial; novel; pathogenic bacteria; programs; scaffold; 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/项目主任（倒数第一中）：Mahmud, Taifo - 2 R01 AI61528-05A1

项目成果

Genetic insights into pyralomicin biosynthesis in Nonomuraea spiralis IMC A-0156.

对Nonomuraea spiralis imc A-0156中黄毛质素生物合成的遗传见解。

• DOI: 10.1021/np400159a
• 发表时间: 2013-05-24
• 期刊: Journal of natural products
• 影响因子: 5.1
• 作者: Flatt PM;Wu X;Perry S;Mahmud T
• 通讯作者: Mahmud T

Structure of a sedoheptulose 7-phosphate cyclase: ValA from Streptomyces hygroscopicus.

• DOI: 10.1021/bi5003508
• 发表时间: 2014-07-08
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Kean KM;Codding SJ;Asamizu S;Mahmud T;Karplus PA
• 通讯作者: Karplus PA

Progress in aminocyclitol biosynthesis.

• DOI: 10.1016/j.cbpa.2009.02.030
• 发表时间: 2009-04
• 期刊: CURRENT OPINION IN CHEMICAL BIOLOGY
• 影响因子: 7.8
• 作者: Mahmud, Taifo

The α-ketoglutarate/Fe(II)-dependent dioxygenase VldW is responsible for the formation of validamycin B.

• DOI: 10.1002/cbic.201200464
• 发表时间: 2012-10-15
• 期刊: CHEMBIOCHEM
• 影响因子: 3.2
• 作者: Almabruk, Khaled H.;Asamizu, Shumpei;Chang, Ada;Varghese, Sheril G.;Mahmud, Taifo
• 通讯作者: Mahmud, Taifo

Biosynthetic gene cluster of cetoniacytone A, an unusual aminocyclitol from the endosymbiotic Bacterium Actinomyces sp. Lu 9419.

• DOI: 10.1002/cbic.200800527
• 发表时间: 2009-01-26
• 期刊: CHEMBIOCHEM
• 影响因子: 3.2
• 作者: Wu, Xiumei;Flatt, Patricia M.;Xu, Hui;Mahmud, Taifo
• 通讯作者: Mahmud, Taifo