Oxidized mucus proteinase inhibitor: a fairly potent neutrophil elastase inhibitor
Open accessAbstract
N-chlorosuccinimide oxidizes one of the methionine residues of mucus proteinase inhibitor with a second-order rate constant of 1.5 M-1.s-1. Cyanogen bromide cleavage and NH2-terminal sequencing show that the modified residue is methionine-73, the P′1 component of the inhibitor's active centre. Oxidation of the inhibitor decreases its neutrophil elastase inhibitory capacity but does not fully abolish it. The kinetic parameters describing the elastase-oxidized inhibitor interaction are: association rate constant kass. = 2.6 x 10(5) M-1.s-1, dissociation rate constant kdiss. = 2.9 x 10(-3) s-1 and equilibrium dissociation constant Ki = 1.1 x 10(-8) M. Comparison with the native inhibitor indicates that oxidation decreases kass. by a factor of 18.8 and increases kdiss. by a factor of 6.4, and therefore leads to a 120-fold increase in Ki. Yet, the oxidized inhibitor may still act as a potent elastase inhibitor in the upper respiratory tract where its concentration is 500-fold higher than Ki, i.e. where the elastase inhibition is pseudo-irreversible. Experiments in vitro with fibrous human lung elastin, the most important natural substrate of elastase, support this view: 1.35 microM elastase is fully inhibited by 5-6 microM oxidized inhibitor whether the enzyme-inhibitor complex is formed in the presence or absence of elastin and whether elastase is pre-adsorbed on elastin or not.
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SLPI and elafin potencies are diminished, though not completely abolished, under oxidative conditions due to methionine residues in their protease binding loops.
“Although not completely abolished, the potencies of SLPI and elafin are diminished under oxidative conditions, due to the similar presence of methionine residues in their protease binding loops [16,17].”
From Discrimination of Methionine Sulfoxide and Sulfone by Human Neutrophil Elastase (2021) · cites this paper as [16]
The paper identifies mucus proteinase inhibitor (MPI) as SLPI and reports in the Discussion (page unavailable) that oxidation of Met-73 in its inhibitory-site loop diminishes anti-elastase activity without abolishing it. The cited paper does not address elafin, so it does not support extending that finding or its proposed mechanism to elafin. (LLM, conf=0.88)
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Research works printed but not linked: 3
- Bieth, J. G. (1986) in Regulation of Matrix Accumulation (Mecham, R. P., ed.), pp. 217-320, Academic Press, New York
- Rudolphus, A., Heinzel-Wieland, R., Vincent, V. A. M. M., Saunders, D., Steffens, G. J., Dijkman, J. H. and Kramps, J. A. (1991a) Clin. Sci. 81, 777-784
- Thompson, R. C. and Ohisson, K. (1986) Proc. NatI. Acad. Sci. U.S.A. 83, 6692-6696
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Discrimination of Methionine Sulfoxide and Sulfone by Human Neutrophil Elastase
Leahy, D., Grant, C., Jackson, A., Duff, A., Tardiota, N., Van Haeften, J., Chen, X., Peake, J. M., Kruppa, M. D., Smith, E. T., et al. (2021) · Molecules · doi:10.3390/molecules26175344 · Cited by 2 · see citing works
“Although not completely abolished, the potencies of SLPI and elafin are diminished under oxidative conditions, due to the similar presence of methionine residues in their protease binding loops [16,17].”
Background
- Authors
- Boudier, C., & Bieth, J. G.
- Affiliations
- Inserm (FR)
- ORCID
- Boudier, C
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 1994-10-01
- Volume
- 303
- Issue
- 1
- Pages
- 61-68
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC1137557
- OpenAlex
- W2285469021
- Cited by
- 47
- References
- 0
- Citations by year
- 2023: 1 · 2021: 3 · 2020: 2 · 2017: 1 · 2015: 1 · 2013: 2 · 2012: 3
- FWCI
- 0.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- 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
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Keywords
- neutrophil elastase, protein oxidation, N-chlorosuccinimide, dissociation constant, lung elastin, upper respiratory tract, protease inhibitors
- MeSH terms
- Amino Acid Sequence, Binding Sites, Cyanogen Bromide, Humans, Kinetics, Mathematics, Methionine, Models, Theoretical, Molecular Sequence Data, Oxidation-Reduction, Pancreatic Elastase, Peptide Fragments, Proteins, Sputum, Succinimides, Serine Proteinase Inhibitors, Leukocyte Elastase, Proteinase Inhibitory Proteins, Secretory
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