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: 1308151
• 负责人: Coran Watanabe
• 金额: $ 30.8万
• 依托单位: Texas A&M 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 2017-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1308151&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.

通过这一奖项，生命过程化学项目资助了来自德克萨斯农工大学的Coran Watanabe博士和康奈尔大学的Stephen Ealick博士，他们将合作对氮霉素生物合成途径的酶进行功能和结构上的表征。具体而言，该项目旨在评估硫酯酶结构域相互作用伙伴和迭代聚酮合成酶（PKS） AziB的结构表征，以及AziA2和azabycle生物合成酶的功能表征。本项目还旨在了解细菌I型迭代聚酮合成酶（PKS）的结构，该酶参与了azinomycin naphthoate的构建。虽然长期以来人们一直认为所有的细菌芳香聚酮都来自II型PKS，但现在很清楚，情况并非如此，阿嗪霉素PKS是一个具体的例子。因此，azinomycin PKS将作为这种细菌I型迭代PKS类的模型系统。实验将阐明前所未有的结构域结构（C-PCP-C）的不寻常的非核糖体肽合成酶（NRPS）模块的关键作用。叠氮霉素还含有一个叠氮环系统，其生物合成尚不清楚。这些研究应该通过对四种酶的功能表征来深入了解氮化吡啶形成的途径和机制。天然产物或次生代谢物是由特定生物体产生的化合物，但对宿主的生存不是必需的。这类化合物通常具有强大的生物活性，可作为开发治疗剂的先导化合物。这里正在研究氮霉素的生物合成。氮霉素是一类具有抗肿瘤活性的DNA交联剂。从长远来看，了解大自然如何构建这些紧张的环系统将有助于揭示生物合成中的一个基本机制问题，并为治疗目的的途径基因工程铺平道路。该项目还包括一个外联部分，本科生和高中生将接触到天然产品的研究。