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Kinetics and physiologic relevance of the inactivation of alpha 1-proteinase inhibitor, alpha 1-antichymotrypsin, and antithrombin III by matrix metalloproteinases-1 (tissue collagenase), -2 (72-kDa gelatinase/type IV collagenase), and -3 (stromelysin).

Publication ,  Journal Article
Mast, AE; Enghild, JJ; Nagase, H; Suzuki, K; Pizzo, SV; Salvesen, G
Published in: J Biol Chem
August 25, 1991

Serpins encompass a superfamily of proteinase inhibitors that regulate many of the serine proteinases involved in inflammation and hemostasis. In vitro, many serpins are catalytically inactivated by proteinases that they do not inhibit, leading to the concept of proteolytic down-regulation of serpin inhibitory capacity. The extent to which down-regulation of serpin activity occurs in vivo is debated, since little is known of the rates at which the process occurs. To address this debate, we have measured the rates of inactivation of three serpins, alpha 1-proteinase inhibitor (alpha 1PI), alpha 1-antichymotrypsin (alpha 1ACT), and antithrombin III (ATIII), by three human matrix metalloproteinases (MMPs-1, -2, and -3) thought to be involved in tissue destruction and repair. Our object was to establish a working kinetic model which can be used to predict whether serpin inactivation by these proteinases is likely to occur in vivo. We determined the rates of inactivation of these three serpins by each of the MMPs and compared these to rates of inhibition of the MMPs by an endogenous inhibitor, alpha 2-macroglobulin. An equation designed to predict the extent of substrate hydrolyzed by an enzyme in the presence of an enzyme inhibitor gave the following predictions of the inactivation in vivo: (i) ATIII is unlikely to be inactivated by the MMPs. (ii) MMP-2 (72-kDa gelatinase/type IV collagenase) is unlikely to inactivate any of the three serpins. (iii) MMP-1 (tissue collagenase) will inactivate alpha 1PI and alpha 1ACT only when its concentration saturates that of its controlling inhibitors. (iv) MMP-3 (stromelysin) may inactivate small amounts of alpha 1PI and more significant amounts of alpha 1ACT, even in the presence of its controlling inhibitors. Any physiologic or pathologic inactivation of these serpins by these MMPs that occurs in vivo will probably be due to MMP-3, and will likely only take place in tissues and inflammatory loci where the concentration of MMP inhibitors is depressed.

Duke Scholars

Published In

J Biol Chem

ISSN

0021-9258

Publication Date

August 25, 1991

Volume

266

Issue

24

Start / End Page

15810 / 15816

Location

United States

Related Subject Headings

  • alpha 1-Antitrypsin
  • alpha 1-Antichymotrypsin
  • Substrate Specificity
  • Pepsin A
  • Molecular Sequence Data
  • Microbial Collagenase
  • Metalloendopeptidases
  • Matrix Metalloproteinase 3
  • Matrix Metalloproteinase 1
  • Kinetics
 

Citation

APA
Chicago
ICMJE
MLA
NLM

Published In

J Biol Chem

ISSN

0021-9258

Publication Date

August 25, 1991

Volume

266

Issue

24

Start / End Page

15810 / 15816

Location

United States

Related Subject Headings

  • alpha 1-Antitrypsin
  • alpha 1-Antichymotrypsin
  • Substrate Specificity
  • Pepsin A
  • Molecular Sequence Data
  • Microbial Collagenase
  • Metalloendopeptidases
  • Matrix Metalloproteinase 3
  • Matrix Metalloproteinase 1
  • Kinetics