Halogenation Biochemistry in Human and Environmental Health

人类和环境健康中的卤化生物化学

基本信息

批准号：
10655356
负责人：
Vinayak Agarwal
金额：
$ 37.38万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-04-30
项目状态：
未结题

项目摘要

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.

项目摘要海洋中的生物过程在环境和人类中引入了各种卤代分子展示体。这些卤代分子中的一些具有有利的药物活性有吸引力的候选药物虽然许多自然产生的海洋卤素分子是有效的毒素和污染物。在生物，分子和原子水平上了解这些卤代分子在海洋中自然构建是研究的主要动机此处描述的程序。很好地验证了海藻和过滤海洋底栖无脊椎动物（例如海绵）卤代天然产物的生产者异常多产。与原核生物相反生物化学，我们对这些真核生物如何生物合成天然产品的理解要少得多由于在培养和遗传询问这些生物方面的挑战而发展。这是关键该提议寻求解决的科学挑战，以便提供海藻和海绵来源使用生物遗传学手段的卤素产物。这里设想的进度取决于两个关键的知识驱动因素。第一个是测序真核转录组而不是基因组来规避真核基因组复杂性。这第二个驱动力是根据从中间体设计的天然产品生物合成方案未靶向的代谢组数据集，然后使用这些合理的方案指导真核的采矿生物合成酶发现的转录组。具体而言，卤代中间体和卤代酶在此工作流程中用作诊断特征。基因组学，生物化学，合成生物学和代谢组学的跨学科能力允许计划参与者不仅要询问生物遗传途径以生产海洋真核生物 - 衍生的卤化药剂团和污染物，但也使用锁定的遗传暗物质海洋霍洛比昂宏基因组可产生新的卤代分子，有利药物生物活性。程序设计还包含发现和表征的机会新的卤化酶学和适应卤素酶作为通用生物催化剂。描述的研究这两个分子都集中在这两个分子中，因为这将导致对关键的卤素如何理解的卤代分子的理解兴趣是在海洋海绵生物群体中建立的，同时同时接受方法发展和工程机会。