The overarching theme of this long-standing project is both a comprehensive and in depth understanding of the biology of arsenic, the most pervasive environmental toxic substance and carcinogen in nature. The Environmental Protection Agency calls arsenic the most prevalent environmental toxin and carcinogen in the United States (www.atsdr.cdc.gov/cercla/07list.html). Arsenic causes cardiovascular and peripheral vascular diseases, neurological disorders, diabetes mellitus and various forms of cancer such as skin and bladder cancer. We have described steps in the biogeocycle for inorganic arsenic and identified a parallel biocycle for organoarsenicals. We hypothesize that members of microbial communities synthesize methylarsenite (MAs(III)) by methylation of inorganic arsenite (As(III)) and use this extremely toxic organoarsenical as an antibiotic against other bacteria. Man has created even more toxic synthetic organoarsenicals for use as herbicides and antimicrobial growth promoters. In response to environmental pressures, bacteria evolved resistance mechanisms against both biological and synthetic toxic organoarsenicals. Our overall goal is to characterize the pathway of arsenic methylation and detoxification at the functional, mechanistic and structural levels. We propose three specific aims: 1) synthesis of MAs(III), 2) breakdown of MAs(III) and 3) efflux of MAs(III). We unify these physiological functions in a new and novel hypothesis on the evolution of antibiotics.

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. 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
Research Project (R01)
Project #
5R01GM055425-36
Application #
9730478
Study Section
Prokaryotic Cell and Molecular Biology Study Section (PCMB)
Program Officer
Anderson, Vernon
Project Start
1997-05-01
Project End
2021-06-30
Budget Start
2019-07-01
Budget End
2021-06-30
Support Year
36
Fiscal Year
2019
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
Packianathan, Charles; Li, Jiaojiao; Kandavelu, Palani et al. (2018) Reorientation of the Methyl Group in MAs(III) is the Rate-Limiting Step in the ArsM As(III) S-Adenosylmethionine Methyltransferase Reaction. ACS Omega 3:3104-3112
Packianathan, Charles; Kandavelu, Palani; Rosen, Barry P (2018) The Structure of an As(III) S-Adenosylmethionine Methyltransferase with 3-Coordinately Bound As(III) Depicts the First Step in Catalysis. Biochemistry 57:4083-4092
Chen, Jian; Yoshinaga, Masafumi; Rosen, Barry P (2018) The antibiotic action of methylarsenite is an emergent property of microbial communities. Mol Microbiol :
Huang, Ke; Xu, Yan; Packianathan, Charles et al. (2018) Arsenic methylation by a novel ArsM As(III) S-adenosylmethionine methyltransferase that requires only two conserved cysteine residues. Mol Microbiol 107:265-276
Zhang, Jun; Xu, Yan; Cao, Tingting et al. (2017) Arsenic methylation by a genetically engineered Rhizobium-legume symbiont. Plant Soil 416:259-269
Pawitwar, Shashank S; Nadar, Venkadesh S; Kandegedara, Ashoka et al. (2017) Biochemical Characterization of ArsI: A Novel C-As Lyase for Degradation of Environmental Organoarsenicals. Environ Sci Technol 51:11115-11125
Hao, Xiuli; Li, Xuanji; Pal, Chandan et al. (2017) Bacterial resistance to arsenic protects against protist killing. Biometals 30:307-311
Chen, Jian; Li, Jiaojiao; Jiang, Xuan et al. (2017) Conserved cysteine residues determine substrate specificity in a novel As(III) S-adenosylmethionine methyltransferase from Aspergillus fumigatus. Mol Microbiol 104:250-259
Zhu, Yong-Guan; Xue, Xi-Mei; Kappler, Andreas et al. (2017) Linking Genes to Microbial Biogeochemical Cycling: Lessons from Arsenic. Environ Sci Technol 51:7326-7339
Chen, Song-Can; Sun, Guo-Xin; Rosen, Barry P et al. (2017) Recurrent horizontal transfer of arsenite methyltransferase genes facilitated adaptation of life to arsenic. Sci Rep 7:7741

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