MECHANISMS OF ARSENIC TRANSPORT AND BIOTRANSFORMATIONS

砷转运和生物转化机制

• 批准号: 10595533
• 负责人: BARRY P. ROSEN
• 金额: $ 46.32万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 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/10595533
• 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; 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; Qualifying; 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

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，EPA认为是一个 最重要的对人类健康的潜在环境威胁。砷暴露是癌症的原因 疾病，儿童发育延迟，并破坏人类微生物组。我们的研究计划 在我们的纽约赠款的当前资金期间开花，重点关注砷运输商 和生物转化，可以改变其可用性，物种形成，流动性和毒性。我们是独特的 有资格参加该项目：在这笔赠款的一生中，我的小组确定并表征了大多数 ARS基因/蛋白质参与砷运输，生物转化和抗性及其对它们的影响 全球砷生物地球细胞。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，开发了生物传感器 有机苯苯甲酸除草剂并发现了有机苯苯甲状腺素，有可能成为新颖的抗菌素 代理商。我未来五年的目标分为四类。 1）酶的结构/功能分析 砷生物转化。我们将阐明ARSM砷S-的催化循环 腺苷甲硫代（SAM）甲基转移酶，Arsh甲基氧化酶，ARSI C-AS键裂解酶 以及通过生化和结构分析的ARSN N-乙酰转移酶。 2）调节和生物传感。 我们将确定冶金调节的结构细节。我们将设计新的传感应用程序 环境有机苯乙污染物。 3）砷转运蛋白；我们确定了许多新的腐蚀 对于有机苯乙烯，将通过分子遗传学组合确定转运机理， 生物化学和晶体学。 4）砷抗生素；我们最近确定了两个有机苯苯甲型的自然 具有抗生素活性的产品。我们将确定合成的途径和 这些新颖的化合物并发现具有潜在健康应用的新天然产品。我的整体 Vision是一项具有足够广度的研究计划，以涵盖对生理作用的识别 已知的砷耐药基因和足够的深度以阐明其分子机制。微生物 基因组具有许多非特征的砷相关基因。有预测的腐蚀和酶 没有已知的底物或功能。我们预测这些涉及砷运输或生物转化。 我们将为新ARS基因挖掘微生物基因组，推断出其进化史并确定它们如何 影响环境砷的循环。我们将发现他们的生理功能。他们的蛋白质 产品将通过生化和结构分析纯化和特征。我的总体主题是 为理解全球砷生物地球细胞及其对全球砷的影响做出重大贡献 人类健康。