Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using 20 strains of Pseudomonas aeruginosa isolated from patients, production of protease, elastase, and collagenase was determined by shaking culture in either complex or semisynthetic medium. No collagenase was produced by any strain of P. aeruginosa. According to their production of protease and elastase in different media, the P. aeruginosa strains were divided into three groups: the first group can produce elastase in complex medium and both protease and elastase in semisynthetic medium; the second group cannot produce any proteolytic enzymes in complex medium but can produce any proteolytic enzymes in either medium; and the third group cannot produce any proteolytic enzymes in either medium. In spite of the differences in the ability of the strains to produce the enzymes, depending upon the origin of the strains, the protease or elastases produced in different broths were regarded as identical.
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PMID:Production of protease and elastase by Pseudomonas aeruginosa strains isolated from patients. 1 45

Gross, light microscopic, and electron microscopic examination of the rabbit corneal destruction produced by experimental Pseudomonas aeruginosa infections revealed a combination of acute inflammation and liquefaction necrosis of the cornea. Degeneration of the epithelial cells and the start of polymorphonuclear leukocyte infiltration of the cornea occurred initially. These changes were followed by loss of the epithelium, degeneration and loss of the keratocytes and endothelium, loss of the characteristic weblike pattern of the proteoglycan ground substance, dispersal of ultrastructurally normal collagen fibrils, extensive accumulation followed by degeneration of polymorphonuclear leukocytes, and accumulation of plasma proteins and fibrin in the necrotic cornea. Histochemical examination of the cornea suggested a loss of the proteoglycan ground substance but not of collagen. Rabbit corneas injected with Clostridium histolyticum collagenase showed gross and cellular changes similar to those observed during the pseudomonal infections; however, histochemical examination suggested a loss of collagen, and electron microscopy revealed ultrastructurally abnormal collagen fibrils. The results support the idea (i) that a bacterial or host-derived collagenase is not required for extensive corneal damage during a P. aeruginosa corneal infection, and (ii) that a P. aeruginosa corneal infection may severly damage the cornea by producing extensive corneal edema and by causing the loss of the corneal proteoglycan ground substance, thus resulting in dispersal of undamaged collagen fibrils, weakening of the cornea, and subsequent descemetocele formation and corneal perforation by the anterior chamber pressure.
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PMID:Rabbit corneal damage produced by Pseudomonas aeruginosa infection. 16 2

The hydroxamic acid HONHCOCH2CH(i-Bu)CO-L-Trp-NHMe, isomer 6A (GM 6001), inhibits human skin fibroblast collagenase with Ki of 0.4 nM using the synthetic thiol ester substrate Ac-Pro-Leu-Gly-SCH(i-Bu)CO-Leu-Gly-OEt at pH 6.5. The other isomer, 6B, which has the opposite configuration at the CH2CH(i-Bu)CO alpha-carbon atom, has a Ki of 200 nM for this enzyme. GM 6001 is one of the most potent inhibitors of human skin fibroblast collagenase yet reported. GM 6001 has a Ki of 20 nM against thermolysin and Pseudomonas aeruginosa elastase. Isomer 6B has a Ki of 7 nM against thermolysin and 2 nM against the elastase. 6A and 6B are the most potent hydroxamate inhibitors reported for these bacterial enzymes. The pattern of inhibition for all three enzymes suggests that isomer 6A is the (R,S) compound, stereochemically analogous to the L,L-dipeptide, and isomer 6B is the (S,S) compound, analogous to the DL-dipeptide. The tolerance of the D configuration by thermolysin and the elastase allows these inhibitors to discriminate between the human and bacterial enzymes simply by inversion of configuration at the CH2CH(i-Bu)CO alpha-carbon atom. Substitution of the potential metal liganding groups carboxylate and hydrazide for the hydroxamate group yields much weaker inhibitors for all three enzymes.
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PMID:Inhibition of human skin fibroblast collagenase, thermolysin, and Pseudomonas aeruginosa elastase by peptide hydroxamic acids. 132 94

Substitution of the phosphonamidate linkage (PO2-NH) for the peptide bond (CO-NH) in substrate-like sequences produces inhibitors of human skin fibroblast collagenase with Ki's far below Km for the native collagen substrate. Using a thiol ester substrate at pH 6.5, phthaloyl-GlyP-Ile-Trp-(S)NHCH-(Me)Ph, the phosphonamidate analog of phthaloyl-Gly-Ile-Trp-(S)NHCH(Me)Ph, has a Ki of 20 nM. Peptide phosphonamidates with amino acid sequences extended further to the right or the left of the Gly-Ile-Trp sequence had higher Ki's. Substitution of the phosphinate linkage (PO2-CH2) for the peptide bond also gives potent inhibitors such as napthoyl-GlyP-C-Leu-Trp-NHBzl, the phosphinate analog of naphtholyl-Gly-Leu-Trp-NHBzl, which has a Ki of 10 nM. Some of the phosphonamidates and phosphinates are also excellent inhibitors of the bacterial zinc metalloproteases thermolysin and Pseudomonas aeruginosa elastase.
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PMID:Inhibition of human skin fibroblast collagenase by phosphorus-containing peptides. 148 35

When human fibroblast collagenase was incubated with ClCH2CO-(N-OH)Leu-Ala-Gly-NH2 (2-5 mM) in Tris buffer, pH 7.4 at 25 degrees C, a slow, time-dependent inhibition of the enzyme was observed. Dialysis against a buffer to remove free inhibitor did not reactivate the enzyme. A reversible competitive inhibitor, phthaloyl-GlyP-Ile-Trp-NHBzl (50 microM) partially protected the enzyme from inactivation by the compound. From the concentration dependent rates of inactivation Ki = 0.5 +/- 0.1 mM and k3, the rate constant for inactivation = 3.4 +/- 0.3 x 10(-3) min-1 were determined. The inactivation followed the pH optimum (6.5-7.0) for the enzyme activity, suggesting direct involvement of the same active site residue(s). The reaction mode of the inhibitor may be analogous to that of the inactivation of Pseudomonas aeruginosa elastase [Nishino, N. and Powers, J. (1980) J. Biol. Chem., 255, 3482] in which the catalytic glutamate carboxyl was alkylated by the inhibitor after its binding to enzyme through the hydroxamic Zn2+ ligand. All carboxyl groups in the inactivated collagenase were modified with 0.1 M ethyl dimethylaminopropyl carbodiimide/0.5 M glycinamide in 4 M guanidine at pH 5. The inactivator-affected carboxyl group was then regenerated with 1 M imidazole at pH 8.9, 37 degrees C for 12 h and the protein was radiolabeled with 3H-glycine methyl ester and carbodiimide to incorporate 0.9 residue glycine per mol enzyme.
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PMID:Inactivation of human fibroblast collagenase by chloroacetyl N-hydroxypeptide derivatives. 166 36

Tetracycline has anticollagenase activity in human and animal tissues. Recent evidence shows collagenase to be instrumental in the progression of infectious and noninfectious corneal ulceration. We investigated the effect of systemic tetracycline on the incidence of corneal perforation in Pseudomonas aeruginosa ulcerative keratitis in rabbits. Twenty rabbits were assigned randomly to two groups in a masked fashion. All corneas were inoculated with 10(6) P. aeruginosa organisms. Ten rabbits (20 eyes) received intramuscular tetracycline 50mg/kg/day in a saline vehicle (treatment group), and ten rabbits (20 eyes) received saline alone (control group) for ten days. The incidence of corneal perforation in the treatment group (45%) was significantly lower than that in the control group (80%, P less than .02). This appeared to be independent of any antimicrobial effect from tetracycline. Administration of tetracycline may be a useful adjunct in the treatment of P. aeruginosa corneal ulcers.
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PMID:Effect of systemic tetracycline on progression of Pseudomonas aeruginosa keratitis in the rabbit. 211 13

Pseudomonas aeruginosa elastase is a zinc metalloproteinase which is released during P. aeruginosa infections. Pseudomonas keratitis, which occurs following contact lens-induced corneal trauma, can lead to rapid, liquefactive necrosis of the cornea. This destruction has been attributed to the release of both host-derived enzymes and the bacterial products P. aeruginosa elastase, alkaline protease, exotoxin A, and lipopolysaccharide endotoxin. A synthetic metalloproteinase inhibitor, HSCH2 (DL)CH[CH2CH(CH3)2]CO-Phe-Ala-NH2, which we previously showed to be a potent inhibitor of corneal collagenase and alkali-induced corneal ulceration, was tested as a potential inhibitor of P. aeruginosa elastase. Inhibition constants (Kis) for the resolved diastereomers were determined with the chromogenic substrate furylacryloyl-glycyl-L-leucyl-L-alanine. One isomer had a Ki of 0.3 microM, while the other had a Ki of 0.4 microM. The more potent diastereomer was evaluated in vivo in experimentally induced Pseudomonas keratitis in rabbits. Following inoculation of one cornea of each rabbit, topical treatment with a 1 mM solution of the inhibitor significantly delayed the onset of corneal melting and perforation, as compared with the results for the control and gentamicin-treated groups. This protective effect suggests that the inhibitor may have a therapeutic application by delaying the progression of corneal destruction in Pseudomonas keratitis.
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PMID:Inhibition of Pseudomonas aeruginosa elastase and Pseudomonas keratitis using a thiol-based peptide. 212 41

Protease-deficient mutants of Pseudomonas aeruginosa obtained by ethyl methane sulphonate treatment were found to show pleiotropic effect on various extracellular toxin activities. Of eight mutants five were completely deficient in lecithinase and four in collagenase activity. The decreased hemolytic activity was obtained in five mutants and enterotoxin activity in seven mutants as compared to parent strain.
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PMID:Pleiotropic changes in the activities of extracellular toxins of Pseudomonas aeruginosa protease-deficient mutants. 248 46

Factors influencing pathogenicity of various microbes found in the female lower genital tract remain incompletely understood. Protease production by cervico/vaginal microorganisms may alter or inactivate a variety of proteins important in host defense and structural-functional integrity including collagen-containing chorioamniotic membranes and uterine cervix. Host tissues may be made more susceptible to other organisms' virulence factors by protease-producing members of genital tract local flora. Microorganisms themselves may also be influenced by the presence of other microbial protease. Nonspecific protease, gelatinase, collagenase, and elastase production was examined for in vitro with use of aerobic (30) and anaerobic (25) strains of microorganisms typical of those isolated from the lower genital tract of women with premature rupture of membranes, chorioamnionitis, and puerperal infection. Microorganisms including Bacteroides bivius, Bacteroides melaninogenicus, Bacteroides fragilis, Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Proteus species, and Propionibacterium acnes produce various proteases. Protease production by both acknowledged pathogenic and commensal bacteria may contribute to the occurrence of reproductive tract morbidity including premature rupture of membranes and preterm labor.
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PMID:Protease production by microorganisms associated with reproductive tract infection. 300 13

Actively growing aerobic and anaerobic bacteria were screened by a plate assay, with reconstituted guinea pig collagen as a substrate, for their ability to produce a collagenolytic factor. Collagenolytic activity was not demonstrated among the aerobic organisms tested, with the exception of one strain of Staphylococcus aureus (only when grown under anaerobic conditions). Collagenolytic activity, however, was detected in cultures of Clostridium tetani and Bacteroides species other than B. melaninogenicus. Collagenolytic activity of these organisms could be confirmed by measuring the amount of hydroxyproline liberated from the collagen gel during growth. Although collagenase production by Pseudomonas aeruginosa has been suggested in previous reports, our results were negative. An extracellular fraction of P. aeruginosa was able to hydrolyze a synthetic hexapeptide Cbz-glycyl-l-prolyl-glycyl-glycyl-l-prolyl-l- alanine, but was without detectable effect on reconstituted collagen.
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PMID:Collagenolytic activity of bacteria. 430 39


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