Collaborative Research: Unveiling the Enigmatic Biosynthetic Machinery of the Azinomycins

合作研究：揭开阿嗪霉素神秘的生物合成机制

• 批准号: 1308222
• 负责人: Steven Ealick
• 金额: $ 10万
• 依托单位: Cornell University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1308222&HistoricalAwards=false
• 关键词: Collaborative; Research; Unveiling; Enigmatic; Biosynthetic

With this award, the Chemistry of Life Processes Program is funding Dr. Coran Watanabe from Texas A&M University and Dr. Stephen Ealick of Cornell University to collaboratively characterize enzymes of the azinomycin biosynthetic pathway both functionally and structurally. Specifically, this project is directed at the evaluation of thioesterase-domain interacting partners and structural characterization of the iterative polyketide synthase (PKS) AziB, as well as functional characterization of both AziA2, and the of azabicycle biosynthetic enzymes. This project also aims at a structural understanding of the bacterial Type I iterative polyketide synthase (PKS) involved in the construction of the azinomycin naphthoate. While it was long thought that all bacterial aromatic polyketides are derived from Type II PKSs, it is now clear that this is not the case and the azinomycin PKS serves as a specific example. The azinomycin PKS will thus serve as a model system for this bacterial Type I iterative PKS class. Experiments will elucidate the key role of an unusual non-ribosomal peptide synthetase (NRPS) module of unprecedented domain architecture (C-PCP-C). The azinomycins also contain an aziridine ring system, the biosynthesis of which is poorly understood. These studies should provide inroads into the route and mechanism of aziridine formation through the functional characterization of four enzymes of this pathway. Natural products or secondary metabolites are compounds that are produced by a given organism but are not essential to the survival of the host. Such compounds often possess potent bioactivities and serve as lead compounds for the development of therapeutic agents. The biosynthesis of the azinomycins is under investigation here. The azinomycins are a family of DNA crosslinking agents with demonstrated anti-tumor activity. Understanding how nature constructs these strained ring systems should shed light on a fundamental mechanistic question in biosynthesis and also pave the way for the engineering of the pathway genes for therapeutic purposes, in the longer term. This project also includes an outreach component where both undergraduate and high school students will be exposed to natural products research.

有了这个奖项，生命过程的化学计划正在资助来自德克萨斯州A M大学的Coran Watanabe博士和康奈尔大学的Stephen Ealick博士合作表征azinomycin生物合成途径的酶的功能和结构。 具体而言，该项目是针对硫酯酶结构域相互作用的合作伙伴和迭代聚酮合酶（PKS）AziB的结构表征，以及AziA 2和氮杂双环戊二烯生物合成酶的功能表征的评价。 该项目还旨在了解细菌I型迭代聚酮合酶（PKS）的结构，参与了萘甲酸阿嗪霉素的构建。虽然长期以来认为所有细菌芳香族聚酮衍生自II型PKS，但现在清楚的是，情况并非如此，并且azinomycin PKS作为一个具体的例子。因此，azinomycin PKS将作为这种细菌I型迭代PKS类的模型系统。 实验将阐明一个不寻常的非核糖体肽合成酶（NRPS）模块前所未有的结构域架构（C-PCP-C）的关键作用。阿奇霉素还含有氮丙啶环系统，其生物合成知之甚少。 这些研究应提供的途径和氮丙啶形成的机制，通过这一途径的四个酶的功能特性的进展。天然产物或次级代谢产物是由给定生物体产生的但对宿主的生存不是必需的化合物。 此类化合物通常具有有效的生物活性，并作为开发治疗剂的先导化合物。 azinomycins的生物合成正在研究中。 azinomycins是一个DNA交联剂家族，具有抗肿瘤活性。 了解自然界如何构建这些紧张的环系统应该阐明生物合成中的基本机制问题，并为长期治疗目的的途径基因工程铺平道路。 该项目还包括一个外展部分，本科生和高中生都将接触到天然产品的研究。