Bromine Is an Essential Trace Element for Assembly of Collagen IV Scaffolds in Tissue Development and Architecture

Abstract

Summary 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 post-translational 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 while 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.

Proprotein Convertase Processing Enhances Peroxidasin Activity to Reinforce Collagen IV

“…Peroxidases use hydrogen peroxide (H 2 O 2 ) to oxidize halide ions (X Ϫ ϭ I Ϫ , Br Ϫ , Cl Ϫ ) and form hypohalous acids (HOX). Pxdn preferentially generates HOBr as a reactive intermediate to form sulfilimine cross-links in collagen IV, which represents the first known function for the element bromine (4,9). Given its critical function in the synthesis of basement membranes, it is no surprise that peroxidasin is found throughout the animal kingdom, whereas other animal heme peroxidases are restricted to vertebrates (10,11).…”

Essential trace element analysis of human breast milk

“…It has been proposed that bromine is masked by iodine and chlorine in chemical analyses (109). Recently, it has been discovered that bromine in the form of bromide plays a vital role in membrane integrity at cellular concentrations (59). Very few studies report bromine and its roles in human health.…”

“…Bromine has only recently been recognised as an essential trace element in humans (59). It is classified in the halogen group similar to iodine, fluorine and chlorine and its chemical properties are comparable to other halogens.…”

“…Bromine has been recently identified as essential in humans (59). Data regarding deficiency in humans is currently unavailable.…”

“…Recent findings have also identified that bromine is a newly recognised essential element owing to its role in cellular membrane structure (59). Maret has emphasised recently that the specific meaning of "essential" needs to refer to a biological species (60).…”