Collagenase specificity

Collagenase specifically catalyzes the hydrolysis of collagen, and is used in debridement of dermal ulcers and bums (191). It, like chymopapain, is also useful in the treatment of herniated lumbar disks (192,193). The rationale for collagenase treatment in this instance is based on the preponderance of collagen in herniated disk tissue, and the inability of other enzymes to dissolve collagen (194). 

The matrix metalloendoproteinases (MMPs or matrixins) are a family of zinc and calcium dependent extracellular proteases that collectively degrade most of the protein constituents of the extracellular matrix [9]. There are at least 23 members of this family and are divided primarily on the basis of sequence homology and substrate specificity into the following grouping collagenases (MMP-1, -8, -13, -18) gelatinases... 

Stams T, Spurlino JC, Smith DL, Wahl RC, Ho TF, Qoronfleh MW, Banks TM. Structure of human neutrophil collagenase reveals large Si specificity pocket. Nat Struct Biol 1994 1 119-123. 

Correlation of Certain Proteases with Metastatic Potential in Model Tumor Systems. A variety of different proteases have been found to correlate with metastatic potential in model tumor systems. Many of these early studies were carried out with B16 mouse melanoma cells. Variants of these cells with different metastatic potential have been selected. In separate experiments, total PA activity, CB activity, and collagenase IV activity have all been found to correlate with metastatic potential in these cells (A4, D6). More recently, levels of mRNA for CB have also been found to correlate with metastasis in these melanoma cells (Ql). Correlations also exist between levels of specific proteases and metastatic ability in a number of other model systems see Table 2 (D6). 

Collectively, the MMP are capable of degrading all of the major protein constituents of the extracellular matrix. The interstitial collagenases that are the focus of this review dissolve collagen fibrils by making a single scission across all three a. chains at a specific, sensitive locus of exposed type I, II... 

While this is in principle a valid approach to collagenase inhibitor design, there is some question as to whether or not the assumptions on which this model is based are valid. Specifically, there are several reasons for challenging the assumption that collagenases prefer substrate conformations that mimic those found in collagen. First, an examination of a model of collagen... 

Murphy G, Allan JA, Willenbrock, F, Cockett MI, Docherty AJP. The role of the C-terminal domain in collagenase and stromelysin specificity. J. Biol. Chem. 1992 267 9612-9618. 

Bode W, Reinemer P, Huber R, Kleine T, Schnierer S, Tschesche H. The X-ray crystal structure of the catalytic domain of human neutrophil collagenase inhibited by a substrate analogue reveals the essentials for catalysis and specificity. EMBO J. 1994 13 1263-1269. 

Netzel-Amett S, Fields G, Birkdal-Hansen H, Avan Wart HE. Sequence specificities of human fibroblast and neutrophil collagenases. J. Biol. Chem. 1991 206 6747-7855. 

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