W-Health: Tungsten is an Essential Metal for a Healthy Gut Microbiome

项目摘要/摘要 美国国立卫生研究院人类微生物组计划(HMP)彻底改变了我们对人类的看法- 微生物的相互作用，为研究提供了巨大的推动力，以便获得更多 更深入地了解微生物如何影响人类健康。HMP的肠道微生物 参考基因组和人类胃肠道细菌培养物库包含961个 计142属的物种。然而，人们对这些微生物知之甚少。 在这里，我们将检验一种假设，即钨(W)，一种在生物上几乎从未考虑过的金属 系统，对人体肠道微生物群的健康至关重要。我们的生物信息学分析 揭示了大量这些肠道微生物含有编码不同成员的基因 含W氧化还原酶(WOR)家族。只有极少数WOR酶具有 以前的特征是，主要来自外来的嗜热微生物。该计划的总体目标 拟议的研究是为了表明WOR家族的其他成员在 肠道微生物群。在初步研究中，我们已经表明，一些肠道微生物会携带痕迹 大量的W和它们的含W的Wors去除了活性和潜在的有毒醛 在肠道中发现的，是熟食和微生物代谢产生的。其他W- 含有虫草的化合物被认为可以催化其他未知的反应。在建议的 研究我们将用W监测(使用电感耦合等离子体质谱)提纯10种新的系统发育不同的蠕虫 厌氧层析。它们的催化活性和生理底物将 由酶诱导代谢组学方法测定(使用LC-MS)。此外，我们 提出其中一些蠕虫是同时偶联的电子分叉酶 放能和放能反应，这是最近发现的一种能量守恒机制 生物系统。动力学、光谱(使用EPR)和结构(使用CryoEM)分析 这个W-酶的子集将被用来研究分支反应的性质。vbl.使用 基于基因组的代谢重建，各种蠕虫的生理功能将 我们将确定W对肠道微生物代谢的影响， 包括它们对肠道和烹饪相关醛的抵抗力。

Project Summary/Abstract The NIH Human Microbiome Project (HMP) revolutionized our perspective on human- microbe interactions and provided a tremendous impetus for research in order to obtain a much deeper understanding of how microbes impact human health. The gut microorganisms of the HMP Reference Genomes and the Human Gastrointestinal Bacteria Culture Collection contain 961 species representing 142 genera. Yet, relatively little is known about these microorganisms. Herein we will test the hypothesis that tungsten (W), a metal almost never considered in biological systems, is essential for the health of the human gut microbiome. Our bioinformatics analyses reveal that a large number of these gut microbes contain genes encoding diverse members of the W-containing oxidoreductase (WOR) family of enzymes. Only a very few WOR enzymes have been previously characterized, mainly from exotic thermophilic microbes. The overall goal of the proposed research is to show that other members of the WOR family have essential functions in the gut microbiome. In preliminary studies, we have shown that some gut microbes take up trace amounts of W and their W-containing WORs remove reactive and potentially toxic aldehydes found in the gut, which are generated from cooked foods and microbiome metabolism. Other W- containing WORs are proposed to catalyze other as yet unknown reactions. In the proposed research we will purify ten novel phylogenetically distinct WORs by W-monitored (using ICP-MS) anaerobic chromatography. Their catalytic activities and physiological substrates will be determined by an enzyme-induced metabolomics approach (using LC-MS). In addition, we propose that some of these WORs are electron bifurcating enzymes that simultaneously couple exergonic and endergonic reactions, a recently discovered mechanism of energy conservation in biological systems. Kinetic, spectroscopic (using EPR) and structural (using cryoEM) analyses of this subset of W-enzymes will be used to investigate the nature of the bifurcation reactions. Using genome-based metabolic reconstructions, the physiological functions of the various WORs will be ascertained and we will determine the effects of W on the metabolism of the gut microbes, including on their resistance to gut- and cooking-related aldehydes.