{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T07:01:07Z","timestamp":1760598067911,"version":"build-2065373602"},"reference-count":43,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2021,9,2]],"date-time":"2021-09-02T00:00:00Z","timestamp":1630540800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Human neutrophil elastase (HNE) is a uniquely destructive serine protease with the ability to unleash a wave of proteolytic activity by destroying the inhibitors of other proteases. Although this phenomenon forms an important part of the innate immune response to invading pathogens, it is responsible for the collateral host tissue damage observed in chronic conditions such as chronic obstructive pulmonary disease (COPD), and in more acute disorders such as the lung injuries associated with COVID-19 infection. Previously, a combinatorially selected activity-based probe revealed an unexpected substrate preference for oxidised methionine, which suggests a link to oxidative pathogen clearance by neutrophils. Here we use oxidised model substrates and inhibitors to confirm this observation and to show that neutrophil elastase is specifically selective for the di-oxygenated methionine sulfone rather than the mono-oxygenated methionine sulfoxide. We also posit a critical role for ordered solvent in the mechanism of HNE discrimination between the two oxidised forms methionine residue. Preference for the sulfone form of oxidised methionine is especially significant. While both host and pathogens have the ability to reduce methionine sulfoxide back to methionine, a biological pathway to reduce methionine sulfone is not known. Taken together, these data suggest that the oxidative activity of neutrophils may create rapidly cleaved elastase \u201csuper substrates\u201d that directly damage tissue, while initiating a cycle of neutrophil oxidation that increases elastase tissue damage and further neutrophil recruitment.<\/jats:p>","DOI":"10.3390\/molecules26175344","type":"journal-article","created":{"date-parts":[[2021,9,2]],"date-time":"2021-09-02T23:05:12Z","timestamp":1630623912000},"page":"5344","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Discrimination of Methionine Sulfoxide and Sulfone by Human Neutrophil Elastase"],"prefix":"10.3390","volume":"26","author":[{"given":"Darren","family":"Leahy","sequence":"first","affiliation":[{"name":"School of Biomedical Science, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cameron","family":"Grant","sequence":"additional","affiliation":[{"name":"School of Biomedical Science, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex","family":"Jackson","sequence":"additional","affiliation":[{"name":"School of Biomedical Science, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex","family":"Duff","sequence":"additional","affiliation":[{"name":"School of Biomedical Science, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4594-473X","authenticated-orcid":false,"given":"Nicholas","family":"Tardiota","sequence":"additional","affiliation":[{"name":"School of Biomedical Science, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Van Haeften","sequence":"additional","affiliation":[{"name":"School of Biomedical Science, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xingchen","family":"Chen","sequence":"additional","affiliation":[{"name":"Centre for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan M.","family":"Peake","sequence":"additional","affiliation":[{"name":"School of Biomedical Science, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael D.","family":"Kruppa","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eliot T.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Stanford School of Medicine, Stanford University, Stanford, CA 94305-5739, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William B.","family":"Lott","sequence":"additional","affiliation":[{"name":"School of Biomedical Science, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan M.","family":"Harris","sequence":"additional","affiliation":[{"name":"School of Biomedical Science, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1172\/JCI110307","article-title":"Role of hydrogen peroxide in neutrophil-mediated destruction of cultured endothelial cells","volume":"68","author":"Weiss","year":"1981","journal-title":"J. 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