title: Human matrix metalloprotease activation by insults of bacterial infection involving proteases and free radicals.
abstract: 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.
authors.affiliation: Department of Microbiology, Kumamoto University School of Medicine, Honjo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Maeda
authors.forename: T
authors.initials: T
authors.lastname: Okamoto
authors.forename: T
authors.initials: T
authors.lastname: Akaike
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism; D001665:Binding Sites; D002729:Chloromercuribenzoates / Q000494:pharmacology; D017364:Collagenases / Q000187:drug effects / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000187:drug effects / Q000378:metabolism*; D005033:Ethylmaleimide / Q000494:pharmacology; D005609:Free Radicals; D006801:Humans; D006868:Hydrolysis; D020781:Matrix Metalloproteinase 1; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9; D010455:Peptides / Q000378:metabolism; D011480:Protease Inhibitors / Q000378:metabolism; D013439:Sulfhydryl Reagents / Q000494:pharmacology; D020245:p-Chloromercuribenzoic Acid
chemical_list: D001426:Bacterial Proteins; D002729:Chloromercuribenzoates; D004792:Enzyme Precursors; D005609:Free Radicals; D010455:Peptides; D011480:Protease Inhibitors; D013439:Sulfhydryl Reagents; D020245:p-Chloromercuribenzoic Acid; D010450:Endopeptidases; D017364:Collagenases; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1; D005033:Ethylmaleimide