Peroxidasin mediates bromination of tyrosine residues in the extracellular matrix

Abstract

Peroxidasin is a heme peroxidase that oxidizes bromide to hypobromous acid (HOBr), a powerful oxidant that promotes the formation of the sulfilimine crosslink in collagen IV in basement membranes. We investigated whether HOBr released by peroxidasin leads to other oxidative modifications of proteins, particularly bromination of tyrosine residues, in peroxidasin-expressing PFHR9 cells. Using stable isotope dilution LC-MS/MS, we detected the formation of 3-bromotyrosine, a specific biomarker of HOBr-mediated protein modification. The level of 3-bromotyrosine in extracellular matrix proteins from normally cultured cells was 1.1 mmol/mol tyrosine and decreased significantly in the presence of the peroxidasin inhibitor, phloroglucinol. A negligible amount of 3-bromotyrosine was detected in peroxidasin-knockout cells. 3-Bromotyrosine formed both during cell growth in culture and in the isolated decellularized extracellular matrix when embedded peroxidasin was supplied with hydrogen peroxide and bromide. The level of 3-bromotyrosine was significantly higher in extracellular matrix than intracellular proteins, although a low amount was detected intracellularly. 3-Bromotyrosine levels increased with higher bromide concentrations and decreased in the presence of physiological concentrations of thiocyanate and urate. However, these peroxidase substrates showed moderate to minimal inhibition of collagen IV crosslinking. Our findings provide evidence that peroxidasin promotes the formation of 3-bromotyrosine in proteins. They show that HOBr produced by peroxidasin is selective for, but not limited to, the crosslinking of collagen IV. Based on our findings, the use of 3-bromotyrosine as a specific biomarker of oxidative damage by HOBr warrants further investigation in clinical conditions linked to high peroxidasin expression. Peroxidasin is a heme peroxidase that oxidizes bromide to hypobromous acid (HOBr), a powerful oxidant that promotes the formation of the sulfilimine crosslink in collagen IV in basement membranes. We investigated whether HOBr released by peroxidasin leads to other oxidative modifications of proteins, particularly bromination of tyrosine residues, in peroxidasin-expressing PFHR9 cells. Using stable isotope dilution LC-MS/MS, we detected the formation of 3-bromotyrosine, a specific biomarker of HOBr-mediated protein modification. The level of 3-bromotyrosine in extracellular matrix proteins from normally cultured cells was 1.1 mmol/mol tyrosine and decreased significantly in the presence of the peroxidasin inhibitor, phloroglucinol. A negligible amount of 3-bromotyrosine was detected in peroxidasin-knockout cells. 3-Bromotyrosine formed both during cell growth in culture and in the isolated decellularized extracellular matrix when embedded peroxidasin was supplied with hydrogen peroxide and bromide. The level of 3-bromotyrosine was significantly higher in extracellular matrix than intracellular proteins, although a low amount was detected intracellularly. 3-Bromotyrosine levels increased with higher bromide concentrations and decreased in the presence of physiological concentrations of thiocyanate and urate. However, these peroxidase substrates showed moderate to minimal inhibition of collagen IV crosslinking. Our findings provide evidence that peroxidasin promotes the formation of 3-bromotyrosine in proteins. They show that HOBr produced by peroxidasin is selective for, but not limited to, the crosslinking of collagen IV. Based on our findings, the use of 3-bromotyrosine as a specific biomarker of oxidative damage by HOBr warrants further investigation in clinical conditions linked to high peroxidasin expression. Peroxidasin is a heme peroxidase that is widely distributed throughout the animal kingdom (1Lázár E. Péterfi Z. Sirokmány G. Kovács H.A. Klement E. Medzihradszky K.F. Geiszt M. Structure-function analysis of peroxidasin provides insight into the mechanism of collagen IV crosslinking.Free Radic. Biol. Med. 2015; 83 (25708780): 273-28210.1016/j.freeradbiomed.2015.02.015Crossref PubMed Scopus (30) Google Scholar, 2Soudi M. Zamocky M. Jakopitsch C. Furtmüller P.G. Obinger C. Molecular evolution, structure, and function of peroxidasins.Chem. Biodivers. 2012; 9 (22976969): 1776-179310.1002/cbdv.201100438Crossref PubMed Scopus (46) Google Scholar, 3Nelson R.E. Fessler L.I. Takagi Y. Blumberg B. Keene D.R. Olson P.F. Parker C.G. Fessler J.H. Peroxidasin: A novel enzyme–matrix protein of Drosophila development.EMBO J. 1994; 13 (8062820): 3438-344710.1002/j.1460-2075.1994.tb06649.xCrossref PubMed Scopus (242) Google Scholar). In mammals, its known physiological function is to catalyze the formation of an essential sulfilimine bond (S=N) between specific methionine and hydroxylysine residues in collagen IV (4Bhave G. Cummings C.F. Vanacore R.M. Kumagai-Cresse C. Ero-Tolliver I.A. Rafi M. Kang J.S. Pedchenko V. Fessler L.I. Fessler J.H. Hudson B.G. Peroxidasin forms sulfilimine chemical bonds using hypohalous acids in tissue genesis.Nat. Chem. Biol. 2012; 8 (22842973): 784-79010.1038/nchembio.1038Crossref PubMed Scopus (173) Google Scholar). This intermolecular bond is crucial for the functionality and integrity of the basement membrane, a specialized form of the extracellular matrix (ECM). The mechanism involves the oxidation of bromide to hypobromous acid (HOBr), which then promotes the crosslink between specific methionine and hydroxylysine residues in the noncollagenous domain (NCD) to join two protomers of collagen IV (5McCall A.S. Cummings C.F. Bhave G. Vanacore R. Page-McCaw A. Hudson B.G. Bromine is an essential trace element for assembly of collagen IV scaffolds in tissue development and architecture.Cell. 2014; 157 (24906154): 1380-139210.1016/j.cell.2014.05.009Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar). Other pathophysiological roles of peroxidasin have been suggested, such as antimicrobial defense (6Li H. Cao Z. Moore D.R. Jackson P.L. Barnes S. Lambeth J.D. Thannickal V.J. Cheng G. Microbicidal activity of vascular peroxidase 1 in human plasma via generation of hypochlorous acid.Infect. Immun. 2012; 80 (22526679): 2528-253710.1128/IAI.06337-11Crossref PubMed Scopus (54) Google Scholar, 7Shi R. Cao Z. Li H. Graw J. Zhang G. Thannickal V.J. Cheng G. Peroxidasin contributes to lung host defense by direct binding and killing of gram-negative bacteria.PLoS Pathog. 2018; 14 (29775486): e100702610.1371/journal.ppat.1007026Crossref PubMed Scopus (11) Google Scholar), redox sensing through interaction with the transcription factor Nrf2 (8Hanmer K.L. Mavri-Damelin D. Peroxidasin is a novel target of the redox-sensitive transcription factor Nrf2.Gene. 2018; 674 (29953917): 104-11410.1016/j.gene.2018.06.076Crossref PubMed Scopus (8) Google Scholar), promotion of angiogenesis (9Medfai H. Khalil A. Rousseau A. Nuyens V. Paumann-Page M. Sevcnikar B. Furtmüller P.G. Obinger C. Moguilevsky N. Peulen O. Herfs M. Castronovo V. Amri M. Van Antwerpen P. Vanhamme L. et al.Human peroxidasin 1 promotes angiogenesis through ERK1/2, Akt and FAK pathways.Cardiovasc. Res. 2018; 115 (29982533): 463-47510.1093/cvr/cvy179Crossref Scopus (16) Google Scholar), and kidney fibrosis (10McCall A.S. Bhave G. Pedchenko V. Hess J. Free M. Little D.J. Baker T.P. Pendergraft 3rd, W.F. Falk R.J. Olson S.W. Hudson B.G. Inhibitory anti-peroxidasin antibodies in pulmonary-renal syndromes.J. Am. Soc. Nephrol. 2018; 29 (30279272): 2619-262510.1681/ASN.2018050519Crossref PubMed Scopus (16) Google Scholar, 11Bhave G. Colon S. Ferrell N. The sulfilimine cross-link of collagen IV contributes to kidney tubular basement membrane stiffness.Am. J. Physiol. Renal Physiol. 2017; 313 (28424209): F596-F60210.1152/ajprenal.00096.2017Crossref PubMed Scopus (50) Google Scholar). Homozygous deletion of peroxidasin causes eye defects (12Khan K. Rudkin A. Parry D.A. Burdon K.P. McKibbin M. Logan C.V. Abdelhamed Z.I. Muecke J.S. Fernandez-Fuentes N. Laurie K.J. Shires M. Fogarty R. Carr I.M. Poulter J.A. Morgan J.E. et al.Homozygous mutations in PXDN cause congenital cataract, corneal opacity, and developmental glaucoma.Am. J. Hum. Genet. 2011; 89 (21907015): 464-47310.1016/j.ajhg.2011.08.005Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar), and high expression has been identified as a determinant of melanoma cell invasion (13Jayachandran A. Prithviraj P. Lo P.H. Walkiewicz M. Anaka M. Woods B.L. Tan B. Behren A. Cebon J. McKeown S.J. Identifying and targeting determinants of melanoma cellular invasion.Oncotarget. 2016; 7 (27172792): 41186-4120210.18632/oncotarget.9227Crossref PubMed Scopus (30) Google Scholar). Mammalian peroxidasin is a typical heme peroxidase that catalyzes the two-electron oxidation of thiocyanate and iodide as well as bromide (14Paumann-Page M. Katz R.S. Bellei M. Schwartz I. Edenhofer E. Sevcnikar B. Soudi M. S. G. Furtmüller P.G. Obinger C. the and mechanism of oxidation of human peroxidasin Biol. Chem. 2017; Full Text Full Text PDF PubMed Scopus Google Scholar). oxidizes typical peroxidase substrates and B. Paumann-Page M. S. V. Furtmüller P.G. Obinger C. of human peroxidasin 1 and with PubMed Scopus Google Scholar). HOBr is a oxidant that with the oxidation of and methionine residues and the of to analysis of the of hypobromous acid with protein PubMed Scopus Google Scholar, of with chemical insight into human Med. Chem. 13 PubMed Scopus Google Scholar). HOBr tyrosine to 3-bromotyrosine and an analysis of the of hypobromous acid with protein PubMed Scopus Google Scholar, Y. A. 3-Bromotyrosine and of protein oxidation by for tissue in J. Scopus Google Scholar). stable and for the formation of HOBr and its with proteins. A is whether the HOBr produced by peroxidasin forms the collagen IV cross-link other Our showed that peroxidasin HOBr as detected by the of to its B. R. Paumann-Page M. of peroxidasin activity in isolated extracellular matrix and direct of hypobromous acid 2018; PubMed Scopus Google Scholar). by the formation of in proteins, we show that the activity of peroxidasin during cell growth and in isolated decellularized leads to HOBr-mediated protein modification. We PFHR9 which cells that of basement membrane proteins. This cell has been in to the of collagen IV (4Bhave G. Cummings C.F. Vanacore R.M. Kumagai-Cresse C. Ero-Tolliver I.A. Rafi M. Kang J.S. Pedchenko V. Fessler L.I. Fessler J.H. Hudson B.G. Peroxidasin forms sulfilimine chemical bonds using hypohalous acids in tissue genesis.Nat. Chem. Biol. 2012; 8 (22842973): 784-79010.1038/nchembio.1038Crossref PubMed Scopus (173) Google Scholar, G. Kovács H.A. E. K. B. H. Geiszt M. crosslinking of collagen IV is of Biol. 2018; PubMed Scopus Google Scholar). PFHR9 cells peroxidasin which is embedded in the matrix and to catalyze the formation of the PFHR9 cells which catalyzes the formation of the sulfilimine crosslink in the collagen IV that during the of in culture (4Bhave G. Cummings C.F. Vanacore R.M. Kumagai-Cresse C. Ero-Tolliver I.A. Rafi M. Kang J.S. Pedchenko V. Fessler L.I. Fessler J.H. Hudson B.G. Peroxidasin forms sulfilimine chemical bonds using hypohalous acids in tissue genesis.Nat. Chem. Biol. 2012; 8 (22842973): 784-79010.1038/nchembio.1038Crossref PubMed Scopus (173) Google Scholar, B. R. Paumann-Page M. of peroxidasin activity in isolated extracellular matrix and direct of hypobromous acid 2018; PubMed Scopus Google Scholar, R.M. M. T.P. Hudson B.G. A sulfilimine bond identified in collagen PubMed Scopus Google Scholar). This crosslink was by Vanacore et R.M. M. T.P. Hudson B.G. A sulfilimine bond identified in collagen PubMed Scopus Google as a between the of and the of in the We the formation of in the of collagen IV in our by the culture and the by and The of the isolated of collagen IV from cells was and The by two sulfilimine in two with 1 and is an of peroxidasin Biol. Chem. Full Text PDF Google Scholar). The crosslinking decreased to in isolated from cells in the presence of from peroxidasin-knockout cells. We then levels in the from PFHR9 cells cultured the and detected using with in and both of detected in from cells the in isolated from peroxidasin-knockout cells Using the the level of in isolated from the cells was to 1.1 mmol/mol tyrosine and decreased significantly to mmol/mol when cells in the presence of formation the for formation in for the formation of during growth of PFHR9 cells cultured in with bromide. that a trace amount of bromide in is in culture as in (5McCall A.S. Cummings C.F. Bhave G. Vanacore R. Page-McCaw A. Hudson B.G. Bromine is an essential trace element for assembly of collagen IV scaffolds in tissue development and architecture.Cell. 2014; 157 (24906154): 1380-139210.1016/j.cell.2014.05.009Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar). The level of increased with bromide and to bromide of formation in the showed that crosslinking was with the trace of bromide in the culture whether is formed on intracellular as well as extracellular proteins, from PFHR9 cells into intracellular and The and by The level of detected in the intracellular mmol/mol was of that in the the level in the was higher levels in increased to when cells in the presence of bromide and decreased when was in from peroxidasin-knockout cells of in and in a We investigated whether peroxidasin embedded in the decellularized promotes was isolated from cells in the presence of and with hydrogen peroxide and bromide. The level of 1 increased significantly in the presence of both bromide and hydrogen but not when was A was for collagen IV crosslinking The levels of increased and with concentrations of bromide and hydrogen peroxide and formation levels an and concentrations of bromide and hydrogen peroxide and of and the concentrations of bromide and hydrogen peroxide on the formation of and sulfilimine in decellularized and in isolated from cells in the presence of for was with and and for the and and the concentrations of for 1 and and the concentrations of for 1 from peroxidasin-knockout cells was as in of by and by and as in with of as in the of not when the to to the is a that with bromide as a for peroxidasin (14Paumann-Page M. Katz R.S. Bellei M. Schwartz I. Edenhofer E. Sevcnikar B. Soudi M. S. G. Furtmüller P.G. Obinger C. the and mechanism of oxidation of human peroxidasin Biol. Chem. 2017; Full Text Full Text PDF PubMed Scopus Google Scholar). we showed that physiological concentrations of thiocyanate with the crosslinking of collagen IV B. R. Paumann-Page M. of peroxidasin activity in isolated extracellular matrix and direct of hypobromous acid 2018; PubMed Scopus Google Scholar). we investigated whether thiocyanate the formation of PFHR9 cells in culture with thiocyanate with bromide and to for The levels of in isolated from the cells decreased from to mmol/mol tyrosine with of thiocyanate in the the with bromide increased the level of and the for inhibition by formation in the was by thiocyanate but to a than tyrosine bromination We the of thiocyanate in the isolated from PFHR9 cells in the presence of was decellularized and with concentrations of thiocyanate in to bromide and hydrogen to the in the cell culture bromination of tyrosine residues in decellularized isolated decreased with of with inhibition the bromide to a higher a in formation but to a than the inhibition of formation In we showed that the formation of the sulfilimine crosslink in collagen IV B. R. Paumann-Page M. of peroxidasin activity in isolated extracellular matrix and direct of hypobromous acid 2018; PubMed Scopus Google Scholar). we whether the formation of to culture to a in in the from to mmol/mol bromide was the level of decreased from to mmol/mol In to the inhibition of formation in the decellularized formation in cell with inhibition in the presence of bromide not We have that HOBr produced by peroxidasin leads to the formation of residues in extracellular proteins as well as sulfilimine in collagen IV. We show that bromination during growth of cells in as well as in isolated decellularized peroxidasin is for the formation of is from the low level in isolated from peroxidasin-knockout cells and the of peroxidasin activity is not to the sulfilimine crosslink in collagen IV but causes other protein In cell the level of increased with bromide but with bromide the of bromination was B. R. Paumann-Page M. of peroxidasin activity in isolated extracellular matrix and direct of hypobromous acid 2018; PubMed Scopus Google Scholar), sulfilimine formation was the of bromide. This for by the trace of bromide in the culture (5McCall A.S. Cummings C.F. Bhave G. Vanacore R. Page-McCaw A. Hudson B.G. Bromine is an essential trace element for assembly of collagen IV scaffolds in tissue development and architecture.Cell. 2014; 157 (24906154): 1380-139210.1016/j.cell.2014.05.009Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar). Our findings that the HOBr produced by peroxidasin a of for the crosslinking of collagen IV but low concentrations of is higher but the physiological of of HOBr and its with other was produced in isolated decellularized when supplied with the peroxidasin substrates bromide and hydrogen of in the as formed during cell growth in but bromide was and the was The isolated a higher bromide for This of the in cell culture of and is that the cellular bromide to a higher than that of the and is during of the is that by is during the of proteins cell which membrane and as well as proteins, and the of collagen IV a the proteins showed higher This is with peroxidasin bromination to the has been to catalyze the crosslinking of collagen IV (4Bhave G. Cummings C.F. Vanacore R.M. Kumagai-Cresse C. Ero-Tolliver I.A. Rafi M. Kang J.S. Pedchenko V. Fessler L.I. Fessler J.H. Hudson B.G. Peroxidasin forms sulfilimine chemical bonds using hypohalous acids in tissue genesis.Nat. Chem. Biol. 2012; 8 (22842973): 784-79010.1038/nchembio.1038Crossref PubMed Scopus (173) Google Scholar). is that activity A low but amount of was detected in the intracellular is to of with proteins, as protein was in the than the and to the level of in the of the protein to have been into the Peroxidasin has been detected in the is and via the (1Lázár E. Péterfi Z. Sirokmány G. Kovács H.A. Klement E. Medzihradszky K.F. Geiszt M. Structure-function analysis of peroxidasin provides insight into the mechanism of collagen IV crosslinking.Free Radic. Biol. Med. 2015; 83 (25708780): 273-28210.1016/j.freeradbiomed.2015.02.015Crossref PubMed Scopus (30) Google Scholar, Z. A. A. A. A. B. Z. E. Kovács K.J. V. Geiszt M. Peroxidasin is and into the extracellular matrix of and J. Full Text Full Text PDF PubMed Scopus Google Scholar), then by A the cell membrane S. Bhave G. Peroxidasin to Biol. Chem. 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). for intracellular formation but further is to whether is the The level of was significantly higher in the of collagen IV than in the whether the in the we that the of the protein of the acids in collagen which for of the proteins in basement R. H. V. H. K. A for the of IV collagen in basement J. PubMed Scopus Google Scholar, M. M. P. Hudson B.G. of for IV collagen assembly in basement Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, G. Blumberg B. M. The for the of collagen IV. of collagen IV Biol. Chem. Full Text PDF PubMed Google Scholar). the was higher in the the of for the bromination of tyrosine in the although the sulfilimine crosslinking by the HOBr produced by peroxidasin in the of collagen other of HOBr not to of et C. C. I. J.E. P. J.H. J. Hudson B.G. Colon S. Bhave G. et of basement S. A. PubMed Scopus Google evidence for in kidney basement our findings of in They detected bromination of a in the collagen IV but as bromination is not to is a peroxidasin than with of and been for with of a form that the peroxidase and (14Paumann-Page M. Katz R.S. Bellei M. Schwartz I. Edenhofer E. Sevcnikar B. Soudi M. S. G. Furtmüller P.G. Obinger C. the and mechanism of oxidation of human peroxidasin Biol. Chem. 2017; Full Text Full Text PDF PubMed Scopus Google Scholar). The of thiocyanate not crosslink collagen thiocyanate crosslinking (5McCall A.S. Cummings C.F. Bhave G. Vanacore R. Page-McCaw A. Hudson B.G. Bromine is an essential trace element for assembly of collagen IV scaffolds in tissue development and architecture.Cell. 2014; 157 (24906154): 1380-139210.1016/j.cell.2014.05.009Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar, B. R. Paumann-Page M. of peroxidasin activity in isolated extracellular matrix and direct of hypobromous acid 2018; PubMed Scopus Google Scholar), as The of inhibition is than from the that peroxidasin have an for of and with proteins. In the thiocyanate formation than collagen IV when to cells in culture to isolated The and with bromide that thiocyanate as a However, thiocyanate with HOBr of with for of with chemical insight into human Med. Chem. 13 PubMed Scopus Google Scholar, P. is an of the killing hypobromous Res. PubMed Scopus Google and bromination by direct our that the of HOBr by physiological levels of which is than HOBr Biol. PubMed Scopus Google Scholar, The of acid in Radic. Res. PubMed Scopus Google Scholar), high thiocyanate concentrations in from the of HOBr the sulfilimine Peroxidasin with a of peroxidase B. Paumann-Page M. S. V. Furtmüller P.G. Obinger C. of human peroxidasin 1 and with PubMed Scopus Google Scholar). bromination activity by the B. Paumann-Page M. S. V. Furtmüller P.G. Obinger C. of human peroxidasin 1 and with PubMed Scopus Google and crosslinking in isolated B. R. Paumann-Page M. of peroxidasin activity in isolated extracellular matrix and direct of hypobromous acid 2018; PubMed Scopus Google Scholar). cultured cells we inhibition of crosslinking formation by high physiological the of such inhibition is to The level of bromination that we detected in proteins was in a levels have been in and clinical of peroxidase Y. A. 3-Bromotyrosine and of protein oxidation by for tissue in J. Scopus Google Scholar, C.F. in PubMed Scopus Google Scholar). although is a biomarker for and than tyrosine analysis of the of hypobromous acid with protein PubMed Scopus Google Scholar, of with chemical insight into human Med. Chem. 13 PubMed Scopus Google Scholar). Peroxidasin catalyze formation R.E. Fessler L.I. Takagi Y. Blumberg B. Keene D.R. Olson P.F. Parker C.G. Fessler J.H. Peroxidasin: A novel enzyme–matrix protein of Drosophila development.EMBO J. 1994; 13 (8062820): 3438-344710.1002/j.1460-2075.1994.tb06649.xCrossref PubMed Scopus (242) Google Scholar). the of is an that modifications to and other to The of such modifications and to Our that peroxidasin activity has for clinical has been in and and as a biomarker of oxidative damage in conditions and C.F. in PubMed Scopus Google Scholar, R.E. R. M. P. peroxidase hypobromous acid in the of stable Radic. Biol. Med. PubMed Scopus Google Scholar, E. S. R. E. R. N. C. et and in the of Radic. Biol. Med. PubMed Scopus Google Scholar, of oxidative in and J. PubMed Scopus Google Scholar, Y. N. N. A. M. M. of in and human using PubMed Scopus Google Scholar, J.A. and in 2011; Full Text Full Text PDF PubMed Scopus Google Scholar). In such the formation of has been to other heme and peroxidase Y. A. 3-Bromotyrosine and of protein oxidation by for tissue in J. 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Our findings the of in clinical and the to the of peroxidasin in oxidative modifications in and from hydrogen peroxide from from from and from Other from cells PFHR9 from the PFHR9 cells using as by Colon and Bhave S. Bhave G. Peroxidasin to Biol. Chem. 2016; Full Text Full Text PDF PubMed Scopus Google and by Bhave from We the by Bhave et (4Bhave G. Cummings C.F. Vanacore R.M. Kumagai-Cresse C. Ero-Tolliver I.A. Rafi M. Kang J.S. Pedchenko V. Fessler L.I. Fessler J.H. Hudson B.G. Peroxidasin forms sulfilimine chemical bonds using hypohalous acids in tissue genesis.Nat. Chem. Biol. 2012; 8 (22842973): 784-79010.1038/nchembio.1038Crossref PubMed Scopus (173) Google Scholar). PFHR9 cells high cells in a culture and in for to the The was with of thiocyanate as The cells with 1 1 and to the from the The was in with and in with was using the The of proteins from a culture was to the noncollagenous was in in and J. J. R. M. M. Hudson B.G. and of the domain of IV of the Biol. Chem. Full Text PDF PubMed Google Scholar). The was by using J. J. P. R.J. Hudson B.G. of the noncollagenous domain of basement membrane Biol. Chem. Full Text PDF PubMed Google Scholar). The was with an of in with for 1 The was and the in the was for The was by and with isolated from cells in the presence of was in and bromide and hydrogen peroxide in to of protein in a of The was for and by 1 Other substrates and the concentrations in A stable isotope dilution was for the and of levels in proteins as Y. A. 3-Bromotyrosine and of protein oxidation by for tissue in J. Scopus Google Scholar, R.E. R. M. P. peroxidase hypobromous acid in the of stable Radic. Biol. Med. PubMed Scopus Google Scholar, and of and 3-bromotyrosine in human by stable isotope dilution PubMed Scopus Google Scholar, K.J. M. J. R. R.M. P. G. promotes and in the lung PubMed Scopus Google Scholar). and to for such as matrix and bromination was by of to and was The two for the isotope and for the and for A typical is in using the and for with and in with for The was by to the acid and with and in acid for was using a and an a of The with with acid for increased to then with the The into a and detected in using The was to and the was to The was and the was The of using A was the for tyrosine and for the We to for with the and Bhave from for the peroxidasin-knockout cell analysis of 3-bromotyrosine extracellular matrix intracellular noncollagenous domain phloroglucinol.

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