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Molecular Biotechnology Sep 2002The function of ancillary domains and modules attatched to the catalytic domain of mutidomain proteases, such as the matrix metalloproteinases (MMPs), are not well... (Review)
Review
The function of ancillary domains and modules attatched to the catalytic domain of mutidomain proteases, such as the matrix metalloproteinases (MMPs), are not well understood. The importance of discrete MMP substrate binding sites termed exosites on domains located outside the catalytic domain was first demonstrated for native collagenolysis. The essential role of hemopexin carboxyl-domain exosites in the cleavage of noncollagenous substrates such as chemokines has also been recently revealed. This article updates a previous review of the role of substrate recognition by MMP exosites in both preparing complex substrates, such as collagen, for cleavage and for tethering noncollagenous substrates to MMPs for more efficient proteolysis. Exosite domain interaction and movements--"molecular tectonics"--that are required for native collagen triple helicase activity are discussed. The potential role of collagen binding in regulating MMP-2 (gelatinase A) activation at the cell surface reveals unexpected consequences of substrate interactions that can lead to collagen cleavage and regulation of the activation and activity of downstream proteinases necessary to complete the collagenolytic cascade.
Topics: Amino Acid Motifs; Binding Sites; Catalysis; Catalytic Domain; Collagen; Fibronectins; Matrix Metalloproteinases; Metalloendopeptidases; Models, Molecular; Protein Folding; Protein Structure, Tertiary; Structure-Activity Relationship; Substrate Specificity
PubMed: 12353914
DOI: 10.1385/MB:22:1:051 -
Current Protocols in Cell Biology Sep 2008Matrix metalloproteinases are a class of enzymes that play an important role in the remodeling of the extracellular matrix in development and cancer metastasis. This...
Matrix metalloproteinases are a class of enzymes that play an important role in the remodeling of the extracellular matrix in development and cancer metastasis. This unit describes a set of methods--cell-mediated dissolution of type-1 collagen fibrils, direct and reverse zymography, enzyme capture based on alpha2-macroglobulin and TIMP-1 and -2, and demonstration of cryptic thiol groups in metalloproteinase precursors--that are used to characterize the functions of matrix metalloproteinases and their inhibitors.
Topics: Animals; Biochemistry; Collagen; Gene Expression; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Rats; Staining and Labeling; Tendons; Tissue Inhibitor of Metalloproteinases; alpha-Macroglobulins
PubMed: 18819088
DOI: 10.1002/0471143030.cb1008s40 -
Gynecologic and Obstetric Investigation 1999Endometrial expression of matrix metalloproteinase (MMP)-3, MMP-7 and MMP-11 occurs during menstrual breakdown and subsequent estrogen-mediated growth, but not during... (Review)
Review
Endometrial expression of matrix metalloproteinase (MMP)-3, MMP-7 and MMP-11 occurs during menstrual breakdown and subsequent estrogen-mediated growth, but not during the secretory phase. These enzymes are suppressed by progesterone treatment. Paracrine factors, including transforming growth factor-beta (TGF-beta) and retinoic acid, are also critical for MMP regulation in the endometrium. In contrast, inflammatory cytokines such as interleukin-1alpha may block or interfere with steroid-mediated MMP regulation at ectopic sites of growth. Using in vitro models, our laboratory has investigated the complex interactions between progesterone and locally produced cytokines that may affect MMP expression during the development of endometriosis. Our results indicate that targeting the regulation of MMPs may represent an appropriate therapeutic strategy for the treatment of endometriosis. Copyrightz1999S. KargerAG,Basel
Topics: Adult; Blotting, Western; Chromatography, Thin Layer; Endometriosis; Endometrium; Estradiol; Female; Gene Expression Regulation, Enzymologic; HeLa Cells; Humans; Interleukin-1; Matrix Metalloproteinase 11; Matrix Metalloproteinase 3; Matrix Metalloproteinase 7; Matrix Metalloproteinases; Menstrual Cycle; Metalloendopeptidases; Progesterone; Transforming Growth Factor beta; Tretinoin
PubMed: 10559659
DOI: 10.1159/000052863 -
Wound Repair and Regeneration :... 2000In urodele amphibian spinal cord regeneration, the ependymal cells lining the central canal remodel the lesion site to favor axonal regrowth. We profiled the production...
In urodele amphibian spinal cord regeneration, the ependymal cells lining the central canal remodel the lesion site to favor axonal regrowth. We profiled the production of matrix metalloproteinases by injury-reactive mesenchymal ependymal cells in vivo and in vitro and found that matrix metalloproteinases are involved in this remodeling process in the axolotl (Ambystoma mexicanum). The production of cell-associated matrix metalloproteinases in vivo was shown to be identical to that in our cultured ependymal cell model system. Activated and zymogen forms of matrix metalloproteinases were identified using zymography, chemical inhibitors of matrix metalloproteinases, and cleavage of propeptides by organomercurials. The principal cellular proteinases consisted of matrix metalloproteinase-2 (gelatinase A) and matrix metalloproteinase-1 (type I collagenase), which display characteristic shifts in molecular weight following proenzyme processing by organomercurials. In addition, ependymal cell conditioned medium contained secreted forms of the enzyme undetectable in situ. Matrix metalloproteinase-9 (gelatinase B) as well as matrix metalloproteinase-2 and matrix metalloproteinase-1 were secreted and casein substrate zymography showed the presence of a small amount of a very high molecular weight matrix metalloproteinase-3 (prostromelysin) secreted into the culture medium. Matrix metalloproteinases were still present at 4 weeks post-lesioning when the ependymal cells have just re-epithelialized, but decreased near the completion of regeneration (8 weeks post-lesioning). Zymography showed no detectable matrix metalloproteinases in unlesioned cord but the presence of tissue inhibitor of metalloproteinase-1 in intact cord was seen by Western blotting. This study shows that matrix metalloproteinases are associated with urodele spinal cord regeneration and validates the use of our ependymal cell tissue culture model system to evaluate ependymal cell behavior during spinal cord regeneration.
Topics: Ambystoma mexicanum; Animals; Collagen; Culture Techniques; Gels; Immunoblotting; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Regeneration; Spinal Cord; Substrate Specificity; Tissue Inhibitor of Metalloproteinase-1
PubMed: 11013020
DOI: 10.1046/j.1524-475x.2000.00282.x -
Wound Repair and Regeneration :... Sep 2021Chronic venous ulcers affect 1% of the adult population and are associated with a marked reduction in quality of life, especially if healing is prolonged. Several matrix...
Chronic venous ulcers affect 1% of the adult population and are associated with a marked reduction in quality of life, especially if healing is prolonged. Several matrix metalloproteinases (MMPs) appear to be involved in the pathophysiology of chronic venous ulcer healing, but their exact role is still unclear. Cyclooxygenase-2 (COX-2) is an important enzyme in prostanoid synthesis, induced during inflammation in chronic venous ulcer. The first aim of our study was to compare the expression of MMP-1, MMP-2, and COX-2 in wound tissue to that in normal skin. The second aim was to observe the expression of the above factors in 29 chronic venous ulcers in 22 patients at the beginning and 4 weeks later in relation to healing rates and final healing outcome after 24 weeks. The enrolled population was divided into two groups, healed and non-healed wounds after 24 weeks. The intensity of expression of MMP-1, MMP-2 and COX-2 was assessed for each ulcer in paired wound biopsy samples and wound size measurements using laser triangulation at the beginning and after 4 weeks of observation. Initial healing rates in the first 4 weeks were calculated and proved to be an important predictive factor of healing in 24 weeks. Decreases in MMP-1 and MMP-2 after 4 weeks of observation were distinct, positive predictors for ulcer healing. Healing odds were 3.7 times higher for a decrease in MMP-1 and 2.1 times higher for a decrease in MMP-2 compared to the healing odds for a non-decrease in MMP-1 and MMP-2. In conclusion, a decrease in MMP-1 and MMP-2, but not COX-2, in wound biopsy samples after 4 weeks of observation can predict better healing of chronic venous ulcer.
Topics: Adult; Chronic Disease; Cyclooxygenase 2; Humans; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Matrix Metalloproteinases; Quality of Life; Ulcer; Varicose Ulcer; Wound Healing
PubMed: 33768649
DOI: 10.1111/wrr.12915 -
Archives of Physiology and Biochemistry Apr 2022Regarding the anti-inflammatory and anti-tumour effects of arginine and its derivatives, this study evaluates matrix metalloproteinase (MMPs) expression in an animal...
Regarding the anti-inflammatory and anti-tumour effects of arginine and its derivatives, this study evaluates matrix metalloproteinase (MMPs) expression in an animal model of breast cancer following administration of octopine. In this study, 40 animals of Balb/C mice were divided into 5 groups: the healthy control, the cancer control, the cancer group receiving 50 mg of octopine, the cancer group receiving 100 mg of octopine and the cancer group receiving 150 mg of octopine for 3 weeks. 4T1 cell line was used to induce cancer. Biopsy specimens were enrolled from mice and , and gene expression evaluated using real-time PCR, while these protein amounts were measured using immunohistochemistry and ELISA methods. Data were analysed using one-way ANOVA, Kruskal-Wallis and Mann-Whitney U tests ( < .05). The results showed that 100 mg octopine consumption had significant decreasing effect on expression ( = .02) in the treatment group compared with cancerous non-treated mice. Furthermore, results from immunohistochemistry and ELISA confirmed this effect, the protein amount of MMP-9 was significantly decreased in group treating with 100 mg octopine (.005). The use of octopine has a beneficial effect on reducing MMP-9 in mice breast cancer.
Topics: Animals; Arginine; Breast Neoplasms; Female; Matrix Metalloproteinase 13; Matrix Metalloproteinase 3; Matrix Metalloproteinase 9; Matrix Metalloproteinases, Secreted; Mice; Mice, Inbred BALB C
PubMed: 31814478
DOI: 10.1080/13813455.2019.1696367 -
Seminars in Cancer Biology Jun 2019Matrix metalloproteinases (MMPs) are members of zinc-dependent endopeptidases implicated in a variety of physiological and pathological processes. Over the decades, MMPs... (Review)
Review
Matrix metalloproteinases (MMPs) are members of zinc-dependent endopeptidases implicated in a variety of physiological and pathological processes. Over the decades, MMPs have been studied for their role in cancer progression, migration, and metastasis. As a result, accumulated evidence of MMPs incriminating role has made them an attractive therapeutic target. Early generations of broad-spectrum MMP inhibitors exhibited potent inhibitory activities, which subsequently led to clinical trials. Unexpectedly, these trials failed to meet the desired goals, mainly due to the lack of efficacy, poor oral bioavailability, and toxicity. In this review, we discuss the regulatory role of MMPs in cancer progression, current strategies in targeting MMPs for cancer treatment including prodrug design and tumor imaging, and therapeutic value of MMPs as biomarkers in breast, lung, and prostate cancers.
Topics: Animals; Biomarkers; Disease Management; Disease Progression; Disease Susceptibility; Gene Expression Regulation, Neoplastic; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Molecular Targeted Therapy; Neoplasms; Signal Transduction; Structure-Activity Relationship
PubMed: 29155240
DOI: 10.1016/j.semcancer.2017.11.008 -
Advances in Protein Chemistry and... 2017Several members of the zinc-dependent matrix metalloproteinase (MMP) family catalyze collagen degradation. Experimental data reveal a collaboration between different MMP...
Several members of the zinc-dependent matrix metalloproteinase (MMP) family catalyze collagen degradation. Experimental data reveal a collaboration between different MMP domains in order to achieve efficient collagenolysis. Molecular dynamics (MD) simulations have been utilized to provide atomistic details of the collagenolytic process. The triple-helical structure of collagen exhibits local regions of flexibility, with modulation of interchain salt bridges and water bridges contributing to accessibility of individual chains by the enzyme. In turn, the hemopexin-like (HPX) domain of the MMP initially binds the triple helix and facilitates the presentation of individual strands to active site in the catalytic (CAT) domain. Extensive positive and negative correlated motions are observed between the CAT and HPX domains when collagen is bound. Ultimately, the MD simulation studies have complemented structural (NMR spectroscopy, X-ray crystallography) and kinetic analyses to provide a more detailed mechanistic view of MMP-catalyzed collagenolysis.
Topics: Animals; Catalytic Domain; Collagen; Crystallography, X-Ray; Humans; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Matrix Metalloproteinase 8; Matrix Metalloproteinases; Molecular Dynamics Simulation; Nuclear Magnetic Resonance, Biomolecular; Protein Conformation; Proteolysis
PubMed: 28683915
DOI: 10.1016/bs.apcsb.2017.04.001 -
Matrix Biology : Journal of the... 2015The development of matrix metalloproteinase (MMP) inhibitors has often been frustrated by a lack of specificity and subsequent off-target effects. More recently,... (Review)
Review
The development of matrix metalloproteinase (MMP) inhibitors has often been frustrated by a lack of specificity and subsequent off-target effects. More recently, inhibitor design has considered secondary binding sites (exosites) to improve specificity. Small molecules and peptides have been developed that bind exosites in the catalytic (CAT) domain of MMP-13, the CAT or hemopexin-like (HPX) domain of MT1-MMP, and the collagen binding domain (CBD) of MMP-2 and MMP-9. Antibody-based approaches have resulted in selective inhibitors for MMP-9 and MT1-MMP that target CAT domain exosites. Triple-helical "mini-proteins" have taken advantage of collagen binding exosites, producing a family of novel probes. A variety of non-traditional approaches that incorporate exosite binding into the design process has yielded inhibitors with desirable selectivities within the MMP family.
Topics: Binding Sites; Enzyme Inhibitors; Humans; Male; Matrix Metalloproteinases; Peptides; Small Molecule Libraries; Substrate Specificity
PubMed: 25595836
DOI: 10.1016/j.matbio.2015.01.002 -
Biochemical Society Symposium 2003The matrix metalloproteinases (MMPs) constitute a family of multidomain zinc endopeptidases which contain a catalytic domain with a common metzincin-like topology. The... (Review)
Review
The matrix metalloproteinases (MMPs) constitute a family of multidomain zinc endopeptidases which contain a catalytic domain with a common metzincin-like topology. The MMPs are involved not only in extracellular matrix degradation, but also in a number of other biological processes. Normally, their proteolytic activity is regulated precisely by their main endogenous protein inhibitors, in particular the tissue inhibitors of metalloproteinases (TIMPs). Disruption of this balance results in serious diseases, such as arthritis, tumour growth and metastasis, rendering the MMPs attractive targets for inhibition therapy. Knowledge of their tertiary structures is crucial for a full understanding of their functional properties. Since the first publication of atomic MMP structures in 1994, much more structural information has become available on details of the catalytic domain, on its interaction with synthetic and protein inhibitors, on domain organization and on the formation of complexes with other proteins. This review will outline our current knowledge of MMP structure.
Topics: Matrix Metalloproteinases; Models, Molecular; Protein Conformation; Structure-Activity Relationship
PubMed: 14587278
DOI: 10.1042/bss0700001