title: Uranium exerts acute toxicity by binding to pyrroloquinoline quinone cofactor.
abstract: Uranium as an environmental contaminant has been shown to be toxic to eukaryotes and prokaryotes; however, no specific mechanisms of uranium toxicity have been proposed so far. Here a combination of in vivo, in vitro, and in silico studies are presented describing direct inhibition of pyrroloquinoline quinone (PQQ)-dependent growth and metabolism by uranyl cations. Electrospray-ionization mass spectroscopy, UV-vis optical spectroscopy, competitive Ca(2+)/uranyl binding studies, relevant crystal structures, and molecular modeling unequivocally indicate the preferred binding of uranyl simultaneously to the carboxyl oxygen, pyridine nitrogen, and quinone oxygen of the PQQ molecule. The observed toxicity patterns are consistent with the biotic ligand model of acute metal toxicity. In addition to the environmental implications, this work represents the first proposed molecular mechanism of uranium toxicity in bacteria, and has relevance for uranium toxicity in many living systems.
authors.affiliation: Department of Chemical and Biological Engineering, Montana State University, Bozeman, Montana 59717-3920, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: VanEngelen
authors.forename: Robert K
authors.initials: RK
authors.lastname: Szilagyi
authors.forename: Robin
authors.initials: R
authors.lastname: Gerlach
authors.forename: Brady D
authors.initials: BD
authors.lastname: Lee
authors.forename: William A
authors.initials: WA
authors.lastname: Apel
authors.forename: Brent M
authors.initials: BM
authors.lastname: Peyton
mesh_terms: D003198:Computer Simulation; D008024:Ligands; D008954:Models, Biological; D008956:Models, Chemical; D045542:PQQ Cofactor / Q000737:chemistry*; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D011848:Radioactive Pollutants / Q000737:chemistry / Q000633:toxicity*; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet; D023382:Toxicity Tests, Acute; D014501:Uranium / Q000737:chemistry / Q000633:toxicity*
chemical_list: D008024:Ligands; D011848:Radioactive Pollutants; D014501:Uranium; D045542:PQQ Cofactor