STUDIES OF BENZ(A)ANTHRAQUINONE ANTIBIOTICS

该计划的具体目标集中在苯[a]蒽醌- 衍生抗生素将继续进行关于卡那霉素的工作 由村山链霉菌产生的抗生素，以及 抗生素PD 116740，由S. WP 4669。一组有限的 实验将在S. rimosus，为了识别 一般矩阵的关键分支点之一， 苯并[a]蒽醌的生物合成， 四曲霉素和四曲古洛的前体/产物关系。 研究设计包括结构研究，以确定更多 生物合成的中间产物。这将由 表征其他代谢物的组合，以及 综合和测试合理的候选人。 在卡那霉素中 途径，代谢物，潜在的中间体将是 通过将已知的中间体提供给目前的37个 被封锁的变种人研究设计将包括生物化学 检测和表征这些途径中的关键酶的研究 (e.g.对于氨基和酰胺基转移酶，芳基环氧酶和 芳基环氧化物水解酶、氢醌环氧化物水解酶和芳香族环氧化物水解酶。 环裂解酶），和分子遗传学研究克隆， 测序并表征所选基因。 这项研究计划的主要目标是了解 自然界中的化学反应以及它们之间的联系 共同产生具有重要生物活性的复杂结构 医学相关活动，尤其是糖尿病。这 目标将通过所描述的多方面的 这种方法将精心挑选的实验融入到合成中， 生物合成、酶学和分子遗传学。这样的 跨学科方法已变得越来越重要， 想要研究新陈代谢的现代生物有机化学家， 规则及其后果。它将为 例如通过代谢和遗传修饰生物活性的应用 通过工程来产生新的分子结构。这 跨学科方法也是培训 新的化学家与生物学的理解和广泛的 解决重要生物化学问题的技能。

The specific aims of this program focus on benz[a]anthraquinone- derived antibiotics. Work will be continued on the kinamycin antibiotics produced by Streptomyces murayamaensis, and on antibiotic PD 116740, produced by S. WP 4669. A limited set of experiments will be carried out in S. rimosus, in order to identify one of the key branch-points in the general matrix of benz[a]anthraquinone biosynthesis by examining the precursor/product relationship of tetrangomycin and tetrangulol. The Research Design includes structural studies to identify more biosynthetic intermediates in each pathway. This will be done by a combination of characterizing additional metabolites, and of synthesizing and testing reasonable candidates. In the kinamycin pathway, metabolites that are potentially intermediates will be identified by feeding known intermediates to a current set of 37 blocked mutants. The Research Design will include biochemical studies to detect and characterize key enzymes in these pathways (e.g. for amino- and amidotransferases, aryl epoxidases and arylepoxide hydrolases, hydroquinone epoxidases, and aromatic ringcleaving enzymes), and molecular genetics studies to clone, sequence, and characterize selected genes. The broad objective of this research program is to understand which chemical reactions are available in Nature and how they are linked together to produce complex structures with significant bio- medically relevant activity, in particular, antibiosis. This objective will be attained through the described multi-faceted approach that blends carefully chosen experiments in synthesis, biosynthesis, enzymology and molecular genetics. Such an interdisciplinary approach has become more and more essential for the modern bioorganic chemist who desires to study metabolism, its regulation and its consequences. It will lay the groundwork for applications such as modifying bioactivity by metabolic and genetic engineering to generate new molecular structures. This interdisciplinary approach is also an effective vehicle to train new chemists with an understanding of biology and a broad range of skills for solving important biochemical problems.