Deciphering the steps of prodiginine biosynthesis

描述（由申请方提供）：原青霉素是由放线菌和其他真细菌产生的线性和环状低聚吡咯红色抗生素家族。这类抗生素的成员已经知道了一段时间，因为它们具有广泛的抗真菌，抗细菌活性。近年来，人们对这些天然产品产生了极大的兴趣，因为它们似乎具有明显的抗疟疾、抗癌和免疫抑制活性。我们通过一系列的遗传和生化实验揭示天蓝色链霉菌基因组中的一组23个红色基因编码一个有趣的和不寻常的途径，导致形成十一烷基普地吉宁和环化衍生物链脲菌素B。该过程的初始阶段涉及与脂肪酸生物合成的复杂界面，这将在具体目标1中进一步研究。后续阶段涉及许多具有不寻常结构和催化活性的多功能和单功能蛋白质，具体目标2 - 4将是我们对这些研究的继续。我们的初步工作也表明，我们可以在S.通过将途径中间体的类似物喂入适当的阻断突变体，或创建杂交生物合成途径（将Red蛋白与具有相似催化活性但不同底物特异性的蛋白交换），来合成腔棘鱼。具体目标5将建立在这些成功的基础上，产生额外的新的Prodiginine结构，并评价其在抗疟疾、免疫抑制剂、抗癌和抗真菌试验中的生物活性。一系列广泛的化学、遗传和生物化学方法将用于这5个特定目标，这些目标解决了我们的长期目标：a）建立对前体生物合成途径酶学的全面理解，以及B）利用这些知识产生新的线性和环状前体结构，用于人类健康的潜在应用。Lay语言描述。一些细菌产生明亮的红色色素（Prodiginines），这些色素显示出许多人类健康应用的前景，包括癌症治疗，抗击疟疾和其他传染病，以及帮助器官移植患者。这项工作将确定这些前体是如何由细菌制造的，并利用这些知识来产生和鉴定具有正确化学性质和生物活性的新前体，以用于可能的临床开发。

DESCRIPTION (provided by applicant): Prodiginines are a family of linear and cyclic oligopyrrole red-pigmented antibiotics produced by actinomycetes and other eubacteria. Members of this class of antibiotics have been known for some time, as have their broad antifungal, antibacterial activity. There has been a dramatic interest in recent years in these natural products as they appear to have pronounced antimalarial, anticancer and immunosuppressant activity. We have used a series of genetic and biochemical experiments to reveal that a cluster of 23 red genes in Streptomyces coelicolor genome encode a fascinating and unusual pathway leading to formation of undecylprodiginine and a cyclized derivative, streptorubin B. The initial stages of this process involve a complex interface with fatty acid biosynthesis which will be further investigated in specific aim 1. Subsequent stages involve numerous multifunctional and monofunctional proteins with unusual architecture and catalytic activities and specific aims 2-4 will be a continuation of our studies on these. Our preliminary work has also demonstrated that we can generate novel cyclic and linear prodiginine analogues in S. coelicolor by either feeding analogues of pathway intermediates to the appropriate blocked mutants, or creation of hybrid biosynthetic pathways (exchanging Red proteins with proteins of similar catalytic activity but different substrate specificities). Specific aim 5 will build on these successes generating additional novel prodiginine structures and evaluating their biological activity in antimalarial, immunosuppressant, anticancer and antifungal assays. A wide array of chemical, genetic and biochemical approaches will be used for these 5 specific aims which address our long term objective of a) building a comprehensive understanding of the enzymology of prodiginine biosynthetic pathways and b) using this knowledge to generate novel linear and cyclic prodiginines structures for potential application in human health. Lay Language Description. Some bacteria produce bright red pigments (prodiginines) which show promise for numerous human health applications including cancer treatment, fighting malaria and other infectious diseases, and helping organ transplant patients. This work will identify how these prodiginines are made by the bacteria and use this knowledge to generate and identify new prodiginines with the correct chemical properties and biological activities for possible clinical development.