Mapping Proteome-Wide Targets of Environmental Chemicals Using Reactivity-Based Chemoproteomic Platforms.
We are exposed to a growing number of chemicals in our environment, most of which have not been characterized in terms of their toxicological potential or mechanisms. Here, we employ a chemoproteomic platform to map the cysteine reactivity of environmental chemicals using reactivity-based probes to mine for hyper-reactive hotspots across the proteome. We show that environmental contaminants such as monomethylarsonous acid and widely used pesticides such as chlorothalonil and chloropicrin possess common reactivity with a distinct set of proteins. Many of these proteins are involved in key metabolic processes, suggesting that these targets may be particularly sensitive to environmental electrophiles. We show that the widely used fungicide chlorothalonil specifically inhibits several metabolic enzymes involved in fatty acid metabolism and energetics, leading to dysregulated lipid metabolism in mice. Our results underscore the utility of using reactivity-based chemoproteomic platforms to uncover novel mechanistic insights into the toxicity of environmental chemicals.
Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
Daniel
D
Medina-Cleghorn
Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
Leslie A
LA
Bateman
Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
Breanna
B
Ford
Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
Ann
A
Heslin
Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
Karl J
KJ
Fisher
Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
Esha D
ED
Dalvie
Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: dnomura@berkeley.edu.
Daniel K
DK
Nomura
D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D002874:Chromosome Mapping; D057930:Click Chemistry; D004785:Environmental Pollutants / Q000633:toxicity*; D006801:Humans; D007668:Kidney / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D055442:Metabolome; D051379:Mice; D020543:Proteome / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D018675:Toxicity Tests / Q000379:methods*
D004785:Environmental Pollutants; D020543:Proteome; D002334:Carnitine O-Palmitoyltransferase