CAREER: New Metalloenzyme-Catalyzed Transformations in Natural Product Biosynthesis

化学、生物工程、环境和运输系统部门的生命过程化学项目以及化学、生物工程、环境和运输系统部门的细胞和生化工程项目将资助普林斯顿大学的Mohammad R.Seyedsayamdost博士在天然产品生物合成过程中发现金属酶进行的新颖反应。天然产物是由各种微生物合成并释放到具有各种生物功能的环境中的小分子。天然产品也是治疗药物的主要来源。金属酶通常与这些分子的产生有关，但它们催化的反应在大多数情况下是未知的。拟议的实验有助于确定在天然产物生物合成过程中由数百种金属酶催化的转化。通过这样做，这项研究扩大了金属酶的化学库，并描绘了新的生物合成策略，可用于商品分子的工业生产。同时，该实验计划为在化学和生物领域进行研究的研究生和本科生提供了严格的培训。该项目被整合到一个旨在提高当地高中教师科学技能的推广计划中。最近微生物基因组序列的爆炸性增长揭示了大量新的金属酶。由于许多酶的底物尚不清楚，挖掘这种令人望而生畏的新颖催化前景是一个巨大的挑战。在这个项目中，一种生物信息学方法被用来将底物与尚未确定特征的金属酶联系起来。然后利用生物实验、核磁共振波谱和质谱学来阐明这些酶所进行的反应。它们的详细机制是光谱和动力学研究的主题。这些研究拓宽了金属酶的反应范围，定义了新的生物合成途径。这一结果将揭示在合成复杂的天然产品过程中，大自然用来催化困难转化的策略。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

With this award, the Chemistry of Life Processes Program in the Chemistry Division and the Cellular and Biochemical Engineering Program in the Division of Chemical, Bioengineering, Environmental and Transport Systems are funding Dr. Mohammad R. Seyedsayamdost from Princeton University to discover novel reactions carried out by metalloenzymes during natural product biosynthesis. Natural products are small molecules synthesized by diverse microorganisms and released into the environment where they have varied biological functions. The natural products are also a major source of therapeutics. Metalloenzymes are often implicated in the production of these molecules, but the reactions that they catalyze are in most cases unknown. The proposed experiments help define the transformations catalyzed by hundreds of metalloenzymes during natural product biosynthesis. In doing so, the research expands the chemical repertoire of metalloenzymes and delineate new biosynthetic strategies, which may be used in the industrial production of commodity molecules. At the same time, the experimental plan enables rigorous training for of graduate and undergraduate students who do research at the interface of chemistry and biology. The project is integrated into an outreach program designed to grow the scientific skills of teachers at local high schools.The recent explosion in microbial genome sequences has brought to light an abundance of new metalloenzymes. With the substrates of many of these enzymes unknown, mining this daunting and novel catalytic landscape is a big challenge. In this project, a bioinformatic approach is used to link substrates to yet uncharacterized metalloenzymes. The reactions carried out by these enzymes are then elucidated using biological experiments, NMR spectroscopy and mass spectrometry. Their detailed mechanisms is the subject of spectroscopic and kinetic studies. These investigations broaden the reaction scope of metalloenzymes and define new biosynthetic pathways. The results will shed light on the strategies that nature utilizes to catalyze difficult transformations during the synthesis of complex natural products.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.