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: 2900493
• 负责人: NICOLA L. B. POHL
• 金额: $ 3.17万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2900493
• 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.

细菌芳香族聚酮脱氢酶（PKS）已经显示出前景 在生产新的改性聚芳族化合物中， 许多抗肿瘤剂如柔红霉素。然而，酶 这些多蛋白复合物的机制仍然不清楚。什么样的 这些PKS耐受的起始单位以及这些引物告诉我们什么 这些蛋白质的机制清楚了解 天然和合成基材的公差，结构 决定聚酮化合物链长的底物的决定因素，以及 扩大现有启动单元的库将提供一个模型， 引导未来的工程工作朝着更大的潜在库发展 治疗学为了测试的结构决定因素， 聚酮化合物链起始单元，其决定其加工性， 最终链长，拟议的研究主要使用纯化的 放线菌紫素（act）PKS作为代表性芳香族PKS系统：1）至 探索PKS接受合成起始单元的能力， 不同的空间参数以测试系统的空间容差; 2)测试PKS接受合成起始单元的能力， 密切模仿自然的起始单位，看看链长是否 由酮的数量或酮的间距决定， 3）探索PKS接受合成链的能力 起始单元是生物电子等排体的经典和非经典生物电子等排体， 4）探讨PKS加工各种N- 乙酰半胱胺衍生的起始单元;和5）克隆另一个高度 来自链霉菌的类似芳香族PKS复合物，其天然使用 丁基或更大的启动器单元，以与ACT系统进行比较和对比， 以及探索更大的合成效用的可能性。