title: Bromine is an essential trace element for assembly of collagen IV scaffolds in tissue development and architecture.
abstract: Bromine is ubiquitously present in animals as ionic bromide (Br(-)) yet has no known essential function. Herein, we demonstrate that Br(-) is a required cofactor for peroxidasin-catalyzed formation of sulfilimine crosslinks, a posttranslational modification essential for tissue development and architecture found within the collagen IV scaffold of basement membranes (BMs). Bromide, converted to hypobromous acid, forms a bromosulfonium-ion intermediate that energetically selects for sulfilimine formation. Dietary Br deficiency is lethal in Drosophila, whereas Br replenishment restores viability, demonstrating its physiologic requirement. Importantly, Br-deficient flies phenocopy the developmental and BM defects observed in peroxidasin mutants and indicate a functional connection between Br(-), collagen IV, and peroxidasin. We establish that Br(-) is required for sulfilimine formation within collagen IV, an event critical for BM assembly and tissue development. Thus, bromine is an essential trace element for all animals, and its deficiency may be relevant to BM alterations observed in nutritional and smoking-related disease. PAPERFLICK:
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, 451 Preston Research Building, Nashville, TN 37232, USA.
authors.forename: A Scott
authors.initials: AS
authors.lastname: McCall
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, 607 Light Hall, Nashville, TN 37232, USA; Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, D-3100 Medical Center North, Nashville, TN 37232, USA.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Cummings
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, D-3100 Medical Center North, Nashville, TN 37232, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Bhave
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, D-3100 Medical Center North, Nashville, TN 37232, USA; Center for Matrix Biology, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN 37232, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Vanacore
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, U-3218 Medical Research Building III, Nashville, TN 37232, USA; Department of Cancer Biology, Vanderbilt University School of Medicine, 691 Preston Research Building, Nashville, TN 37232, USA; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Page-McCaw
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, 607 Light Hall, Nashville, TN 37232, USA; Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, D-3100 Medical Center North, Nashville, TN 37232, USA; Center for Matrix Biology, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN 37232, USA; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, C-3322 Medical Center North, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, 896 Preston Research Building, Nashville, TN 37232, USA. Electronic address: billy.hudson@vanderbilt.edu.
authors.forename: Billy G
authors.initials: BG
authors.lastname: Hudson
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000378:metabolism* / Q000648:ultrastructure; D001966:Bromine / Q000172:deficiency / Q000378:metabolism*; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D004330:Drosophila / Q000254:growth & development* / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007097:Imines / Q000378:metabolism; D007814:Larva / Q000648:ultrastructure; D051379:Mice; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism; D014131:Trace Elements / Q000378:metabolism*; D000097423:Peroxidasin
chemical_list: D001966:Bromine; D003094:Collagen; D016326:Extracellular Matrix Proteins; D007097:Imines; D009195:Peroxidase; D014131:Trace Elements; D000097423:Peroxidasin; C586946:sulfilimine