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 and childhood developmental delay. Our research program focuses 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 that are 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 effect 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.

Public Health Relevance

Arsenic is the most pervasive environmental toxin and carcinogen in the United States, causing cardiovascular and peripheral vascular diseases, neurological disorders, diabetes mellitus and various forms of cancer such as skin and bladder cancer. The overarching theme of this long-standing project is both a comprehensive and in depth understanding of the biology of arsenic, and, in this application we propose to elucidate the genes, enzymes, transporters and mechanisms in the pathways of arsenic biology.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
3R35GM136211-01S1
Application #
10134719
Study Section
Program Officer
Anderson, Vernon
Project Start
2020-04-01
Project End
2025-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Florida International University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
071298814
City
Miami
State
FL
Country
United States
Zip Code
33199