STUDIES OF BENZ(A)ANTHRAQUINONE ANTIBIOTICS

这项计划的具体目标集中在奔驰[a]蒽醌-- 衍生抗生素。对卡那霉素的研究将继续进行 由Murayama链霉菌产生的抗生素 抗生素PD 116740，由S.WP 4669生产。一套有限的 将在S.rimosus进行实验，以确定 的一般矩阵中的关键分支点之一 苯并[a]蒽醌的生物合成 四环素和四环素的前体/产物关系。 研究设计包括结构研究，以确定更多 每条途径中的生物合成中间体。这将由一个 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，潜在的中间代谢物将是 通过将已知的中间体添加到当前的37 被阻止的突变体。研究设计将包括生化 检测和表征这些途径中关键酶的研究 (例如，氨基和氨基转移酶、芳基环氧化物酶和 芳环氧基水解酶、对苯二酚环氧化酶和芳香族 环裂解酶)，以及克隆的分子遗传学研究， 测序，并对选定的基因进行特征描述。 该研究计划的广泛目标是了解哪些 自然界中的化学反应以及它们之间的联系 共同制造出复杂的结构，具有重要的生物 与医学相关的活动，特别是抗菌作用。这 目标将通过描述的多方面来实现 在合成中混合精心选择的实验的方法， 生物合成、酶学和分子遗传学。这样的一种 跨学科的方法已经变得越来越重要 渴望研究新陈代谢的现代生物有机化学家，其 监管及其后果。它将为以下方面奠定基础 应用，如通过代谢和遗传改变生物活性 工程学来产生新的分子结构。这 跨学科的方法也是一种有效的培训手段 新的化学家对生物学有一定的了解，对 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.