Human matrix metalloprotease activation by insults of bacterial infection involving proteases and free radicals

Biol Chem. 1998 Feb;379(2):193-200. doi: 10.1515/bchm.1998.379.2.193.


We found that human matrix metalloproteases (MMPs) may be processed from their proenzyme forms (proMMP) to their active forms by two new and unique mechanisms: Firstly, by bacterial proteases such as Pseudomonas elastase and Vibrio cholerae protease, which cleave off the N-terminal autoinhibitory domain (so-called cysteine switch) from proMMPs. The second mechanism depends on free radical generation by activated polymorphonuclear leukocytes (PMNs). In this case, peroxynitrite (ONOO-) or nitrogen dioxide radical (.NO2), the reaction products of either superoxide (O2.-) or molecular oxygen (O2) and nitric oxide (.NO), are the key reactants. Both O2.- and .NO are generated by activated macrophages and PMNs as a result of immunologic responses involving various proinflammatory cytokines. .NO2 or ONOO- seems to interact with a single cysteine residue in the propeptide autoinhibitory domain, or so-called cysteine switch of proMMPs, thus transforming proMMPs into their active conformation. Furthermore, reactive oxygen species are known to inactivate the alpha1-protease inhibitor (alpha1-PI), a potent neutrophil elastase inhibitor in plasma. In addition, we found that such radicals activate MMPs which degrade and inactivate alpha1-PI by proteolysis. Thus, the activation of MMPs, accompanied by the inactivation of alpha1-PI, will bring about enhanced proteolytic damage to the matrix tissues of the infected sites by both MMPs and elastase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / metabolism
  • Binding Sites
  • Chloromercuribenzoates / pharmacology
  • Collagenases / drug effects
  • Collagenases / metabolism*
  • Endopeptidases / metabolism
  • Enzyme Activation
  • Enzyme Precursors / drug effects
  • Enzyme Precursors / metabolism*
  • Ethylmaleimide / pharmacology
  • Free Radicals
  • Humans
  • Hydrolysis
  • Matrix Metalloproteinase 1
  • Matrix Metalloproteinase 8
  • Matrix Metalloproteinase 9
  • Peptides / metabolism
  • Protease Inhibitors / metabolism
  • Sulfhydryl Reagents / pharmacology
  • p-Chloromercuribenzoic Acid


  • Bacterial Proteins
  • Chloromercuribenzoates
  • Enzyme Precursors
  • Free Radicals
  • Peptides
  • Protease Inhibitors
  • Sulfhydryl Reagents
  • p-Chloromercuribenzoic Acid
  • Endopeptidases
  • Collagenases
  • Matrix Metalloproteinase 8
  • Matrix Metalloproteinase 9
  • Matrix Metalloproteinase 1
  • Ethylmaleimide