Proteolytic inactivation of α1-proteinase inhibitor and α1- antichymotrypsin by oxidatively activated human neutrophil metalloproteinases

P. E. Desrochers, K. Mookhtiar, H. E. Van Wart, Karen Hasty, S. J. Weiss

Research output: Contribution to journalArticle

93 Citations (Scopus)

Abstract

Human neutrophils use the H2O2-myeloperoxidase-chloride system to generate chlorinated oxidants capable of activating metalloproteinase zymogens that hydrolyze not only native and denatured collagens, but also the serine proteinase inhibitor (serpin) α1-proteinase inhibitor (α1PI). To identify the metalloenzyme that hydrolyzes and inactivates α1PI, neutrophil releasates were chromatographed over gelatin-Sepharose and divided into fractions containing either progelatinase or procollagenase. The gelatinase- containing fraction cleaved α1PI in a manner inhibitable by native type V, but not type I, collagen. Conversely, while the collagenase-containing fraction also cleaved α1PI, this activity was inhibited by type I, but not type V, collagen. Because type I and V collagens are competitive substrates for collagenase and gelatinase, respectively, each of the metalloproteinase zymogens were purified to apparent homogeneity and examined for α1PI- hydrolytic activities. Both purified gelatinase and collagenase inactivated α1PI by hydrolyzing the serpin within its active-site loop at the Phe352-Leu353 and Pro357-Met358 bonds, albeit with distinct kinetic properties. Furthermore, purified collagenase, but not gelatinase, cleaved a second serpin, α1-antichymotrypsin, by hydrolyzing the Ala362- Leu363 bond within its active-site loop. These data demonstrate that human neutrophils use chlorinated oxidants to activate collagenolytic metalloproteinases whose substrate specificities can be extended to members of the serpin superfamily.

Original languageEnglish (US)
Pages (from-to)5005-5012
Number of pages8
JournalJournal of Biological Chemistry
Volume267
Issue number7
StatePublished - Jan 1 1992
Externally publishedYes

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Metalloproteases
Gelatinases
Serine Proteinase Inhibitors
Neutrophils
Peptide Hydrolases
Collagenases
Collagen Type V
Enzyme Precursors
Collagen Type I
Oxidants
Catalytic Domain
Substrates
Gelatin
Substrate Specificity
Sepharose
Peroxidase
Chlorides
Collagen
Kinetics

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Proteolytic inactivation of α1-proteinase inhibitor and α1- antichymotrypsin by oxidatively activated human neutrophil metalloproteinases. / Desrochers, P. E.; Mookhtiar, K.; Van Wart, H. E.; Hasty, Karen; Weiss, S. J.

In: Journal of Biological Chemistry, Vol. 267, No. 7, 01.01.1992, p. 5005-5012.

Research output: Contribution to journalArticle

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