Unveiling the Enigmatic Machinery of the Azinomycins

美国国家科学基金会化学部生命过程化学项目资助了Coran M. H. Watanabe和他来自德克萨斯A M大学的研究小组研究了一种天然土壤微生物是如何制造一种名为azinomycin的分子的。该分子是具有癌症治疗潜力的重要一类分子的成员。该研究小组正在研究azinomycins的生物合成，即自然界如何构建这些分子。这些研究不仅将揭示这些分子是如何在自然界中构建的，而且还为将来将这些途径基因用于治疗目的铺平了道路。 这些调查使研究生，本科生和博士后研究员能够在化学生物学和生物技术方面发展广泛的技能。 此外，这项研究被整合到课堂上，学生们通过自己实地收集土壤样品，了解生物活性剂通常来自环境，这些样品用于测定具有抗生素活性的天然产物。 该项目还包括一个外联部分。 高中学生通过关于抗生素和耐药性的讲座和实验室了解天然产物的研究。 为小学生开展了一系列量身定制的活动，以“人与微生物”为中心。“azinomycins是密集功能化和建筑迷人。 该分子的基本框架是通过聚酮合酶/非核糖体肽合成酶（PKS/NRPS）骨架产生的，而氮丙啶并[1，2-a]吡咯烷部分是生物碱衍生的。 从酶学的角度来看，天然产物代表了一个丰富的宝库，可以挖掘不寻常的生物合成转化。 本申请的目的是功能性重建和表征azinomycin生物合成途径的酶，并正在通过三个主要项目领域进行研究：[1] AziB和AziG介导的聚酮环扩增机制的评价，[2] AziA 3的催化作用的评价，以及[3]氮杂双环戊二烯生物合成酶的功能表征。

The National Science Foundation, Chemistry of Life Processes Program in the Chemistry Division funds Dr. Coran M. H. Watanabe and his research group from Texas A&M University to study how a natural soil dwelling microbe makes a molecule known as azinomycin. This molecule is a member of an important class of molecules with cancer treatment potential. The research group is investigating the biosynthesis of the azinomycins, i.e. how nature constructs these molecules. These studies will not only shed light on how these molecules are constructed by nature but also pave the way for future engineering of the pathway genes for therapeutic purposes. These investigations enable graduate students, undergraduate students, and postdoctoral fellows to develop a broad skillset in chemical biology and biotechnology. Moreover, this research is integrated into the classroom where students learn that bioactive agents are often derived from the environment by carrying out their own field collection of soil samples, which are assayed for natural products with antibiotic activity. This project also includes an outreach component. High school students learn about natural products research through a lecture and lab on antibiotics and drug resistance. A tailored set of activities is carried out for elementary school students, which centers on "Man vs. Microbe."The azinomycins are densely functionalized and architecturally fascinating. The basic framework of the molecule is generated through a polyketide synthase/nonribosomal peptide synthetase (PKS/NRPS) skeleton while the aziridino[1,2-a]pyrollidine moiety is alkaloid derived. From an enzymological perspective the natural product represents a rich treasure trove of unusual biosynthetic transformations to be mined. The objective of this application is to functionally reconstitute and characterize enzymes of the azinomycin biosynthetic pathway and is being investigated through three primary project areas: [1] evaluation of the mechanism of polyketide ring expansion mediated by AziB and AziG, [2] evaluation of the catalytic role of AziA3, and [3] functional characterization of azabicycle biosynthetic enzymes.