Halogenation Biochemistry in Human and Environmental Health

人类和环境健康中的卤化生物化学

• 批准号: 10437027
• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10437027
• 关键词: Address; Biochemistry; Biological; Chemicals; Competence; Complex; Data Set; Engineering; Environment; Environmental Health; Environmental Pollutants; Enzymatic Biochemistry; Enzymes; Eukaryota; Genes; Genetic; Genome; Genomics; Halogens; Human; Invertebrates; Metagenomics; Mining; Molecular; Motivation; Natural Products; Nature; Oceans; Organism; Participant; Pathway interactions; Pharmacologic Substance; Porifera; Process; Production; Research; Resources; Route; Scheme; Seaweed; Toxin; base; dark matter; design; diagnostic signature; drug candidate; feeding; halogenation; interest; metabolomics; metagenome; method development; novel; pharmacophore; pollutant; programs; synthetic biology; transcriptome; transcriptomics

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.

项目概要 海洋中的生物过程将各种卤化分子引入环境和人类体内 暴露。其中一些卤代分子具有良好的药物活性，使其 有吸引力的候选药物，而许多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、分子和原子水平上理解这些物质如何 卤化分子是在海洋中自然形成的，是这项研究的主要动机 此处描述的程序。 海藻和滤食性海洋底栖无脊椎动物（例如海绵）已被充分验证 卤化天然产品的生产商异常多产。与原核天然产物相反 生物化学方面，我们对这些真核生物如何生物合成天然产物的了解还少得多 由于培养和遗传研究这些生物体的挑战而开发。这是关键 该提案旨在解决科学挑战，以提供海藻和海绵衍生产品 使用生物遗传手段卤化天然产物。 这里设想的进展取决于两个关键的智力驱动因素。第一个是排序 真核转录组而不是基因组，以规避真核基因组的复杂性。这 第二个驱动力是设计基于从中开采的中间体的天然产物生物合成方案 非目标代谢组数据集，然后使用这些合理化方案来指导真核生物的挖掘 用于发现生物合成酶的转录组。具体而言，卤化中间体和卤化 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使 项目参与者不仅要探究海洋真核生物生产的生物遗传途径 衍生的卤化药效团和污染物，但也使用锁在其中的遗传暗物质 海洋全生物宏基因组可产生具有有利作用的新型卤化分子 药物生物活性。程序设计还包含发现和表征的机会 新的卤化酶学并采用卤化酶作为通用生物催化剂。研究描述 这里是两个分子的焦点，因为它将引导人们了解关键的卤化分子如何 对海洋海绵生物群落产生兴趣，同时拥抱方法开发和 工程机会。