Halogenation Biochemistry in Human and Environmental Health

项目总结 海洋中的生物过程在环境和人类中引入了各种卤化分子 曝光。其中一些卤化分子具有良好的药理活性，使它们 虽然这些天然产生的海洋卤化分子中的许多是有效的，但有吸引力的候选药物 毒素和污染物。在有机体、分子和原子水平上理解这些 卤化分子是在海洋中自然构建的，这是研究的主要动机 在此描述的程序。 海藻和滤食性海洋底栖无脊椎动物，如海绵，被很好地证实是 特别高产的卤化天然产品生产商。与原核生物天然产物相反 生物化学，我们对这些真核生物如何生物合成天然产物的了解要少得多 这是由于在培养和对这些生物进行遗传审讯方面的挑战而开发的。这是关键所在 这项提案试图解决的科学挑战是为了提供海藻和海绵衍生的 使用生物遗传方法进行卤化处理的天然产品。 这里设想的进展是基于两个关键的智力驱动因素。其中第一个是排序 不是基因组，而是真核转录本，以规避真核基因组的复杂性。这个 第二个驱动力是设计基于从以下来源开采的中间体的天然产品生物合成方案 然后使用这些合理化方案来指导真核生物的挖掘 发现生物合成酶的转录本。具体地说，卤化中间体和卤化 在这个工作流程中，酶被用作诊断标志。 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使 项目参与者不仅询问生产海洋真核生物的生物遗传途径- 衍生出卤化的药效团和污染物，但也使用锁定在 海洋全硫代金属基因组生产新的天然卤代分子 药物生物活性。程序设计也包含了发现和描述特性的机会 新的卤化酶学和适应作为通用生物催化剂的卤代酶。已描述的研究 这两个都是以分子为中心的，因为它将导致理解关键的卤化分子是如何 兴趣建立在海洋海绵生物群中，同时伴随着方法开发和 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.