The effects of hypochlorous acid and neutrophil proteases on the structure and function of extracellular superoxide dismutase

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The effects of hypochlorous acid and neutrophil proteases on the structure and function of extracellular superoxide dismutase. / Morales, Karla; Olesen, Mads Nikolaj; Poulsen, Ebbe Toftgaard; Larsen, Ulrike G; Enghild, Jan Johannes; Petersen, Steen Vang.

I: Free Radical Biology & Medicine, Bind 81, 04.2015, s. 38-46.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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@article{e9e0d22f2f834e54a576ead5d5a0742d,
title = "The effects of hypochlorous acid and neutrophil proteases on the structure and function of extracellular superoxide dismutase",
abstract = "Extracellular superoxide dismutase (EC-SOD) is expressed by both macrophages and neutrophils and is known to influence the inflammatory response. Upon activation, neutrophils generate hypochlorous acid (HOCl) and secrete proteases to combat invading microorganisms. This produces a hostile environment where enzymatic activity in general is challenged. In this study, we show that EC-SOD exposed to physiological relevant concentrations of HOCl remains enzymatically active and retains the heparin binding capacity, although HOCl exposure established oxidative modification of the N-terminal region (Met32) and the formation of an intermolecular cross-link in a fraction of the molecules. The cross-linking was also induced by activated neutrophils. Moreover, we show that the neutrophil-derived proteases human neutrophil elastase and cathepsin G cleaved the N-terminal region of EC-SOD irrespective of HOCl oxidation. Although the cleavage by elastase did not affect the quaternary structure, the cleavage by cathepsin G dissociated the molecule to produce EC-SOD monomers. The present data suggests that EC-SOD is stable and active at the site of inflammation and that neutrophils have the capacity to modulate the biodistribution of the protein by generating EC-SOD monomers that can diffuse into tissue.",
author = "Karla Morales and Olesen, {Mads Nikolaj} and Poulsen, {Ebbe Toftgaard} and Larsen, {Ulrike G} and Enghild, {Jan Johannes} and Petersen, {Steen Vang}",
note = "Copyright {\circledC} 2015. Published by Elsevier Inc.",
year = "2015",
month = "4",
doi = "10.1016/j.freeradbiomed.2014.12.027",
language = "English",
volume = "81",
pages = "38--46",
journal = "Free Radical Biology & Medicine",
issn = "0891-5849",
publisher = "Elsevier Inc",

}

RIS

TY - JOUR

T1 - The effects of hypochlorous acid and neutrophil proteases on the structure and function of extracellular superoxide dismutase

AU - Morales, Karla

AU - Olesen, Mads Nikolaj

AU - Poulsen, Ebbe Toftgaard

AU - Larsen, Ulrike G

AU - Enghild, Jan Johannes

AU - Petersen, Steen Vang

N1 - Copyright © 2015. Published by Elsevier Inc.

PY - 2015/4

Y1 - 2015/4

N2 - Extracellular superoxide dismutase (EC-SOD) is expressed by both macrophages and neutrophils and is known to influence the inflammatory response. Upon activation, neutrophils generate hypochlorous acid (HOCl) and secrete proteases to combat invading microorganisms. This produces a hostile environment where enzymatic activity in general is challenged. In this study, we show that EC-SOD exposed to physiological relevant concentrations of HOCl remains enzymatically active and retains the heparin binding capacity, although HOCl exposure established oxidative modification of the N-terminal region (Met32) and the formation of an intermolecular cross-link in a fraction of the molecules. The cross-linking was also induced by activated neutrophils. Moreover, we show that the neutrophil-derived proteases human neutrophil elastase and cathepsin G cleaved the N-terminal region of EC-SOD irrespective of HOCl oxidation. Although the cleavage by elastase did not affect the quaternary structure, the cleavage by cathepsin G dissociated the molecule to produce EC-SOD monomers. The present data suggests that EC-SOD is stable and active at the site of inflammation and that neutrophils have the capacity to modulate the biodistribution of the protein by generating EC-SOD monomers that can diffuse into tissue.

AB - Extracellular superoxide dismutase (EC-SOD) is expressed by both macrophages and neutrophils and is known to influence the inflammatory response. Upon activation, neutrophils generate hypochlorous acid (HOCl) and secrete proteases to combat invading microorganisms. This produces a hostile environment where enzymatic activity in general is challenged. In this study, we show that EC-SOD exposed to physiological relevant concentrations of HOCl remains enzymatically active and retains the heparin binding capacity, although HOCl exposure established oxidative modification of the N-terminal region (Met32) and the formation of an intermolecular cross-link in a fraction of the molecules. The cross-linking was also induced by activated neutrophils. Moreover, we show that the neutrophil-derived proteases human neutrophil elastase and cathepsin G cleaved the N-terminal region of EC-SOD irrespective of HOCl oxidation. Although the cleavage by elastase did not affect the quaternary structure, the cleavage by cathepsin G dissociated the molecule to produce EC-SOD monomers. The present data suggests that EC-SOD is stable and active at the site of inflammation and that neutrophils have the capacity to modulate the biodistribution of the protein by generating EC-SOD monomers that can diffuse into tissue.

U2 - 10.1016/j.freeradbiomed.2014.12.027

DO - 10.1016/j.freeradbiomed.2014.12.027

M3 - Journal article

C2 - 25582887

VL - 81

SP - 38

EP - 46

JO - Free Radical Biology & Medicine

JF - Free Radical Biology & Medicine

SN - 0891-5849

ER -