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.
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.
|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|
|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 :|
|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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