Hypochlorous Acid Oxygenates the Cysteine Switch Domain of Pro-matrilysin (MMP-7)
Open accessAbstract
Myeloperoxidase uses hydrogen peroxide (H2O2) to generate hypochlorous acid (HOCl), a potent cytotoxic oxidant. We demonstrate that HOCl regulates the activity of matrix metalloproteinase-7 (MMP-7, matrilysin) in vitro, suggesting that this oxidant activates MMPs in the artery wall. Indeed, both MMP-7 and myeloperoxidase were colocalized to lipid-laden macrophages in human atherosclerotic lesions. A highly conserved domain called the cysteine switch has been proposed to regulate MMP activity. When we exposed a synthetic peptide that mimicked the cysteine switch to HOCl, HPLC analysis showed that the thiol residue reacted rapidly, generating a near-quantitative yield of products. Tandem mass spectrometric analysis identified the products as sulfinic acid, sulfonic acid, and a dimer containing a disulfide bridge. In contrast, the peptide reacted slowly with H2O2, and the only product was the disulfide. Moreover, HOCl markedly activated pro-MMP-7, an MMP expressed at high levels in lipid-laden macrophages in vivo. Tandem mass spectrometric analysis of trypsin digests revealed that the thiol residue of the enzyme's cysteine switch domain had been converted to sulfinic acid. Thiol oxidation was associated with autolytic cleavage of pro-MMP-7, strongly suggesting that oxygenation activates the latent enzyme. In contrast, H2O2 failed to oxidize the thiol residue of the protein or activate the enzyme. Thus, HOCl activates pro-MMP-7 by converting the thiol residue of the cysteine switch to sulfinic acid. This activation mechanism is distinct from the well-studied proteolytic cleavage of MMP pro-enzymes. Our observations raise the possibility that HOCl generated by myeloperoxidase contributes to MMP activation, and therefore to plaque rupture, in the artery wall. HOCl and other oxidants might regulate MMP activity by the same mechanism in a variety of inflammatory conditions.
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The oxidation and chlorination of proteins, such as matrix metalloproteinases, leads to detrimental vascular remodeling.
“The oxidation and chlorination of proteins, such as matrix metalloproteinases, leads to detrimental vascular remodeling (314).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [314]
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Self-citation
- Authors
- Fu, X., Kassim, S. Y., Parks, W. C., & Heinecke, J. W.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Heinecke, Jay W.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-11
- Volume
- 276
- Issue
- 44
- Pages
- 41279-41287
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2021769399
- Cited by
- 482
- References
- 52
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 19 · 2023: 11 · 2022: 19 · 2021: 13 · 2020: 20 · 2019: 15 · 2018: 13 · 2017: 21 · 2016: 18 · 2015: 19 · 2014: 23 · 2013: 22 · 2012: 30
- FWCI
- 6.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p41rr000954-34, 7r01ag015013-06, DK56341)
- National Institute on Aging (AG 15013)
- National Heart, Lung, and Blood Institute (P01HL029594, HL 29594, HL-64344, R01HL064344, HL54619)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK56341, P30DK056341)
- National Center for Research Resources (RR 00954)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- hypochlorous acid, matrix metalloproteinase-7, matrilysin, myeloperoxidase, thiol oxidation, sulfinic acids, MMP activation, lipid-laden macrophages, atherosclerosis, plaque rupture, hydrogen peroxide, disulfide bond formation
- MeSH terms
- Amino Acid Sequence, Arteriosclerosis, Chromatography, High Pressure Liquid, Cysteine, Enzyme Activation, Enzyme Precursors, Hydrogen Peroxide, Hypochlorous Acid, Molecular Sequence Data, Peroxidase, Oxygen, Spectrophotometry, Ultraviolet, Matrix Metalloproteinase 7, Spectrometry, Mass, Electrospray Ionization
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