Halogenation Biochemistry in Human and Environmental Health

项目摘要 海洋中的生物过程将各种卤化分子引入环境和人体 麻烦这些卤化分子中的一些具有有利的药物活性，使得它们 虽然许多这些天然产生的海洋卤化分子是有效的， 毒素和污染物。在有机体、分子和原子水平上， 卤代分子在海洋中自然形成是这项研究的主要动机 这里描述的程序。 海藻和滤食性海洋底栖无脊椎动物，如海绵， 卤化天然产物的特别多产的生产商。与原核生物的天然产物相反 生物化学，我们对这些真核生物如何生物合成天然产物的理解远不如 由于培养和遗传询问这些生物体的挑战而开发。这是关键 这一提案旨在解决的科学挑战，以提供海藻和海绵衍生的 使用生物遗传方法的卤化天然产物。 这里设想的进展取决于两个关键的智力驱动因素。第一个是测序 真核转录组，而不是基因组，以规避真核基因组的复杂性。的 第二个驱动力是设计天然产物生物合成方案的基础上，从开采的中间体， 非靶向代谢组学数据集，然后使用这些合理化的方案来指导真核生物的挖掘。 用于生物合成酶的发现。具体来说，卤化中间体和卤化 酶在该工作流程中用作诊断标记。 在基因组学、生物化学、合成生物学和代谢组学方面的跨学科能力， 项目参与者不仅要研究海洋真核生物生产的生物遗传途径， 衍生卤化药效团和污染物，但也使用遗传暗物质锁定在 海洋holobiont宏基因组，以产生新的自然卤化分子， 药物生物活性。该计划的设计还包括机会，发现和特点 新的卤化酶学，使卤化酶成为通用的生物催化剂。述研究 这里是两个分子的重点，在这方面，它将导致了解如何关键卤代分子的 对海洋海绵生物群系产生了兴趣，同时也包括方法的发展， 工程机会。

PROJECT SUMMARY Biotic processes in the oceans introduce various halogenated molecules in the environment and in the human exposome. Some of these halogenated molecules possess favorable pharmaceutical activities making them attractive drug candidates while many of these naturally produced marine halogenated molecules are potent toxins and pollutants. Understanding, at the organismal, molecular, and atomistic levels how these halogenated molecules are naturally constructed in the oceans is the principal motivation of the research program described herein. Seaweeds and filter feeding marine benthic invertebrates such as sponges are well validated to be exceptionally prolific producers of halogenated natural products. Contrary to prokaryotic natural product biochemistry, our understanding of how these eukaryotes biosynthesize natural products is far less developed due to challenges in culturing and genetically interrogating these organisms. This is the key scientific challenge that this proposal seeks to address in order to deliver seaweed- and sponge-derived halogenated natural products using biogenetic means. Progress envisaged here is predicated upon two key intellectual drivers. The first of these is the sequencing of eukaryotic transcriptomes, rather than genomes, to circumvent the eukaryotic genome complexity. The second driver is to design natural product biosynthetic schemes based on intermediates that are mined from untargeted metabolomic datasets and then use these rationalized schemes to guide the mining of eukaryotic transcriptomes for biosynthetic enzyme discovery. Specifically, halogenated intermediates and halogenating enzymes are used as diagnostic signatures in this workflow. Interdisciplinary competence in genomics, biochemistry, synthetic biology, and metabolomics allows the program participants to not only interrogate biogenetic pathways for the production of marine eukaryote- derived halogenated pharmacophores and pollutants, but to also use the genetic dark matter locked away in marine holobiont metagenomes to produce new-to-nature halogenated molecules with favorable pharmaceutical bioactivities. The program design also embraces opportunities to discover and characterize new halogenation enzymology and adapt halogenases as general purpose biocatalysts. Research described here is both molecule focused, in that, it will lead to the understanding of how key halogenated molecules of interest are constructed in marine sponge biomes, while concomitantly embracing method-development and engineering opportunities.