NONNATURAL PRODUCTS FROM AROMATIC POLYPETIDE SYNTHASES

来自芳香族多肽合成酶的非天然产物

• 批准号: 2669600
• 负责人: NICOLA L. B. POHL
• 金额: $ 2.5万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-29 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2669600
• 关键词: acetyl coA; biological products; bioreactors; cell free system; drug design /synthesis /production; enzyme complex; fatty acid synthase; macrolide antibiotics

Bacterial aromatic polyketide synthases (PKSs) have already shown promise in producing new modified polyaromatic compounds that mimic the cores of many anti-tumor agents such as daunorubicin. However, the enzymatic mechanisms of these multi-protein complexes remain obscure. What kinds of starter units do these PKSs tolerate and what do these primers tell us about the mechanism of these proteins? A clear understanding of the tolerances of natural and synthetic substrates, the structural determinants of the substrate that dictate polyketide chain length, and an expanded repertoire of available starter units would provide a model to guide future engineering efforts toward larger libraries of potential therapeutics. In order to test the structural determinants of the polyketide chain starter unit that determine its processability and ultimate chain length, the proposed research uses primarily the purified actinorhodin (act) PKS as a representative aromatic PKS system: 1) to explore the ability of the PKS to accept synthetic starter units with different steric parameters to test the steric tolerances of the system; 2) to test the ability of the PKS to accept synthetic starter units that closely mimic the natural starter units to see if the chain length is determined by the number of ketones or the spacing of ketones in the developing chain; 3) to probe the ability of the PKS to accept synthetic starter units that are classical and non-classical bioisosteres of the natural chain; 4) to probe the ability of the PKS to process various N- acetylcysteamine derived starter units; and 5) to clone another, highly similar aromatic PKS complex from Streptomycetes that naturally use a butyl or larger starter unit to compare and contrast to the act system, as well as to explore the possibility of greater synthetic utility.

细菌芳香族聚酮合成酶(PKS)已显示出良好的应用前景 在生产新的改性多芳烃化合物方面，这种化合物模仿 许多抗肿瘤药物，如柔红霉素。然而，酶 这些多蛋白复合体的机制仍不清楚。什么类型的 起始单位是这些PKS耐受的吗？这些引物告诉了我们什么？ 关于这些蛋白质的机制？清醒地认识到 结构材料的天然和合成基材的公差 决定聚酮链长度的底物的决定因素，以及 可用首发单元的扩展曲目将提供一种模式 引导未来的工程工作朝着更大的潜力库发展 治疗学。为了测试结构上的决定因素 确定其加工性聚酮链起始剂单元和 最终链长，建议的研究主要使用提纯的 放线菌素(ACT)PKS作为一种具有代表性的芳香族PKS体系：1)至 探索PKS接受合成启动单元的能力 不同的立体参数，以测试系统的立体公差； 2)测试PKS接受合成起动器的能力 紧密模仿自然的发酵剂单位，看看链的长度是否 由中的酮的数目或酮的间距确定 开发产业链；3)探索PKS接受综合治理的能力 启动子单位是典型的和非经典的生物等位体 自然链；4)探索PKS处理各种N- 乙酰半胱胺衍生的起始单元；以及5)克隆另一个，高度 来自链霉菌的类似的芳香族PKS复合体，自然使用 丁基或更大的起始剂单位与ACT系统进行比较和对比，如 以及探索更大的综合效用的可能性。