MECHANISMS OF ARSENIC TRANSPORT AND BIOTRANSFORMATIONS

砷转运和生物转化机制

基本信息

批准号：
9923901
负责人：
BARRY P. ROSEN
金额：
$ 33.96万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9923901
关键词：
Acetyltransferase Affect Antibiotics Arsenic Arsenicals Arsenites Biochemical Biochemistry Biology Biosensing Techniques Biosensor Cancer Etiology Cardiovascular system Categories Childhood Crystallography Developmental Delay Disorders Diabetes Mellitus Environmental Carcinogens Enzymes Flowers Funding Gene Proteins Genes Goals Grant Health Heart Diseases Herbicides Human Human Microbiome Lyase Malignant Neoplasms Malignant neoplasm of urinary bladder Metabolic Biotransformation Methylation Methyltransferase Molecular Molecular Genetics National Institute of General Medical Sciences Natural Products Oxidases Pathway interactions Peripheral Vascular Diseases Physiological Proteins Recording of previous events Regulation Research Resistance Role Skin Cancer Structure Toxic Environmental Substances Toxic effect Toxin United States Vision antimicrobial drug enzyme structure falls health application microbial genome nervous system disorder novel permease pollutant programs resistance gene

项目摘要

Project Summary/Abstract: Arsenic is the most pervasive toxin, considered by the EPA to be one the most significant potential environmental threats to human health. Arsenic exposure is a cause of cancer, heart disease, childhood developmental delay, and disrupts the human microbiome. Our research program blossomed during the current funding period of our NIGMS grant, focusing on arsenic transporters and biotransformations, which modify its availability, speciation, mobility and toxicity. We are uniquely qualified for this project: over the lifetime of this grant, my group identified and characterized the majority of ars genes/proteins involved in arsenic transport, biotransformations and resistance and their impact on the global arsenic biogeocycle. We discovered enzymes of the arsenic methylation cycle and elucidated mechanisms and structures of the enzymes of biotransformation, developed biosensors for organoarsenicals herbicides and discovered organoarsenicals with the potential to be novel antimicrobial agents. My goals for the next five years fall into four categories. 1) Structure/function analysis of enzymes of arsenic biotransformations. We will elucidate the catalytic cycle of the ArsM arsenite S- adenosylmethione (SAM) methyltransferase, the ArsH methylarsenite oxidases, the ArsI C-As bond lyases and the ArsN N-acetyltransferase through biochemical and structural analysis. 2) Regulation and biosensing. We will determine the structural details of metalloregulation. We will devise new applications for sensing environmental organoarsenical pollutants. 3) Arsenic transporters; we identified a number of new permeases for organoarsenicals and will determine the mechanism of transport by a combination of molecular genetics, biochemistry and crystallography. 4) Arsenical antibiotics; we recently identified two organoarsenical natural products with antibiotic activity. We will determine the pathways of synthesis and mode of action of these novel compounds and discover new natural products with potential health applications. My overall vision is a research program of sufficient breadth to encompass identification of the physiological roles of known arsenic resistance genes and sufficient depth to elucidate their molecular mechanisms. Microbial genomes have many uncharacterized arsenic-related genes. There are predicted permeases and enzymes with no known substrate or function. We predict these are involved in arsenical transport or biotransformations. We will mine microbial genomes for new ars genes, deduce their evolutionary histories and determine how they affect cycling of environmental arsenicals. We will discover their physiological functions. Their protein products will be purified and characterized by biochemical and structural analyses. My overarching theme is to make substantial contributions to understanding of the global arsenic biogeocycle and its impact on human health.

项目摘要/摘要：砷是最普遍的毒素，被 EPA 认为是最常见的毒素之一。对人类健康最重大的潜在环境威胁。砷暴露是癌症、心脏病的一个原因疾病，儿童发育迟缓，并破坏人类微生物群。我们的研究计划在我们 NIGMS 赠款的当前资助期内蓬勃发展，重点关注砷转运蛋白和生物转化，改变其可用性、形态、流动性和毒性。我们是独一无二的符合该项目的资格：在这笔赠款的整个生命周期中，我的小组确定并描述了大多数参与砷转运、生物转化和抗性的ars基因/蛋白质及其对砷的影响全球砷生物地球循环。我们发现了砷甲基化循环的酶并阐明了生物转化酶的机制和结构，开发生物传感器有机砷除草剂并发现了具有新型抗菌潜力的有机砷代理。我未来五年的目标分为四类。 1) 酶的结构/功能分析砷的生物转化。我们将阐明 ArsM 亚砷酸盐 S- 的催化循环腺苷甲硫酮 (SAM) 甲基转移酶、ArsH 甲基亚砷酸氧化酶、ArsI C-As 键裂解酶以及通过生化和结构分析得到的 ArsN N-乙酰转移酶。 2）调节和生物传感。我们将确定金属调节的结构细节。我们将设计新的传感应用环境有机砷污染物。 3）砷转运体；我们发现了一些新的渗透酶对于有机砷，将通过分子遗传学的组合确定运输机制，生物化学和晶体学。 4）含砷抗生素；我们最近发现了两种有机砷天然具有抗生素活性的产品。我们将确定其合成途径和作用方式这些新化合物并发现具有潜在健康应用的新天然产品。我的整体视觉是一个具有足够广度的研究计划，涵盖了对生理作用的识别已知的砷抗性基因和足够的深度来阐明其分子机制。微生物基因组中有许多未表征的与砷相关的基因。有预测的渗透酶和酶没有已知的底物或功能。我们预测它们参与砷运输或生物转化。我们将挖掘微生物基因组中的新 ars 基因，推断它们的进化历史并确定它们如何影响环境砷的循环。我们将发现它们的生理功能。他们的蛋白质产品将通过生化和结构分析进行纯化和表征。我的首要主题是为了解全球砷生物地球循环及其对砷的影响做出重大贡献人类健康。