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:
Subject(s)
Basement Membrane/metabolism , Bromine/metabolism , Drosophila/growth & development , Trace Elements/metabolism , Animals , Basement Membrane/ultrastructure , Bromine/deficiency , Cell Line , Collagen/metabolism , Drosophila/metabolism , Extracellular Matrix Proteins/genetics , Extracellular Matrix Proteins/metabolism , Humans , Imines/metabolism , Larva/ultrastructure , Mice , Peroxidase/genetics , Peroxidase/metabolism , PeroxidasinSubject(s)
Chloramines/toxicity , Daphnia/drug effects , Water Pollutants, Chemical/toxicity , Animals , Bromine/analysis , Bromine/deficiency , Bromine/toxicity , Chloramines/analysis , Drug Interactions , Fluorine/analysis , Fluorine/deficiency , Fluorine/toxicity , Fresh Water , Lethal Dose 50 , Solvents/chemistry , Water Pollutants, Chemical/analysis , Water Supply/analysisABSTRACT
Pathology of congenital bromine deficiency is described in a she-goat whose mother was kept for two years on a bromine deficient diet. Anomalies of the bones and joints of the anterior limbs, disturbances of carbohydrate, lipid and mineral metabolism in the form of liver, kidney and lymph nodes glycogenosis, liver fat degeneration, haemosiderosis of the liver, spleen and lungs were found. Moderate thymomegaly with hyperplasia of the cortex and an increase in the number of Hassal bodies, microcystic ovary transformation, adrenal adenomatosis, cheilitis, flossitis, focal proliferative extracapillary glomerulonephritis were also observed.
