Metalloproteinases

Matrix metalloproteinases (MMP) are a family of 23 structurally related zinc-dependent endopeptidases capable of degrading components of the 

Most MMPs are secreted as a zymogen, and activation involves removal of a lOkDa amino-terminal domain. Once in the active form, their proteolytic activity is inhibited by 

MMPs also act as predictors of recurrence or metastatic risk. High preoperative serum levels of MMP-2 or MMP-3 are predictive of recurrence in patients with advanced urotheliai carcinoma. Furthermore, high levels of MMP-2 in ovarian tumor cells can predict tumor recurrence. The expression of certain MMPs is predictive of metastatic risk. For example, expression of MMP-1 is associated with lymph node metastasis in cervical and peritoneal metastasis in gastric cancer. MMP inhibition may be a therapeutic strategy for cancer.  

Human matrix metalloproteinases may be processed from their proenzyme forms to their active forms by two new and unique mechanisms (Maeda et al. 1998) 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 pro-matrix metalloproteinases. The second mechanism depends on free radical generation by activated polymorphonuclear leucocytes. In this case, peroxyni-trite (ONOO ) or nitrogen dioxide radical ( NOj) are the key reagents. 

Both O2 and NO are generated by activated macrophages and polymorphonuclear leucocytes as a result of immunologic responses involving various proinflammatory cytokines. NOj or ONOO seems to interact with a single cysteine residue in the propeptide autoinhibitory domain, or so called cysteine-switch of pro-matrix metalloproteinases, thus transforming pro-matrix metalloproteinases into their active conformation. 

The C-terminal domain of human macrophage elastase inhibited elastin degradation (Gronski jr. et al. 1996). 

Stromelysin 1 (= matrix metalloproteinase 3) has been imphcated as playing a pivotal role in jointdegrading diseases like arthritis (Hasty et al. 1990, Hembry et al. 1995). Its synthesis by chondrocytes and synoviocytes can be induced by inflammatory mediators like interleukin-1 (Hasty et al. 1990, MacNaul et al. 1990). 

Stromelysin 3 (= matrix metalloproteinase 11) from rat skin has 491 amino acids, and shows 83,95 and 58 % homology with human, mouse and Xeno-pus ST3, respectively (Okada et al. 1997). In contrast to other matrix metalloproteinases, ST3 is secreted into the extracellular space as a potentially active molecule (Pei and Weiss 1995, Santavicca et al. 1996). By in situ hybridisation. Wolf et al. (1993) detected ST3 transcripts specifically in fibroblastic cells in primary breast carcinomas and so did Okada et al. (1997) in fibroblastic cells loca-hsed in the superficial dermis of healing rat skin wounds. 

3 Modulation of Cellular Responses by Metal-containing Drugs 

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Design and therapeutic application of matrix metalloproteinase heterocyclic inhibitors 99CRV2735. 

Marimastat Metalloproteinase inhibitor, inhibits endothelial cell invasion... 

Vascular Indothelial Growth Factor Matrix Metalloproteinases... 

MM P-9 Matric metalloproteinase Decrease of in vivo metastatic ability... 

Enzyme inhibitors (e.g. metalloproteinases, cathepsin K) Purinergic modulators... 

ECEs are metalloproteinases that are homologous to the neutral endopeptidase (NEP, E-24.11, neprilysin) unlike NEP, however, they form disulfide-bonded homodimers. In man, with ECE-1 and ECE-2, two isoforms are known, which are encoded by two separate genes. For ECE-1 four different variants have been identified (ECE-1 a-d), which are generated by the use of alternative promoters (Table 2). The ECE-1 isoforms only differ in their N-terminal amino acid sequence. For ECE-2, a single gene product has been described in... 

Activation of matrix metalloproteinases (MMP) is also involved in vascular and cardiac remodelling. For example, the fibrillar collagen matrix of the heart... 

Matrix Metalloproteinases Tumor Necrosis Factor Apoptosis... 

The enzymatic activity of these potentially harmful enzymes is tightly controlled. Once transcribed into protein, MMPs are expressed as inactive zymogens and require distinct activation processes to convert them into active enzymes. After secretion, MMP-activity is regulated by the noncovalent binding of tissue inhibitors of metalloproteinases ( TIMPs) as shown in Fig. 2 for MMP-2 and TIMP-2. Four TIMPs have been identified so far TIMP-1, TIMP-2, TIMP-3, and TIMP-4. All known MMPs can be inhibited by at least one of the four known TIMPs. Nevertheless, individual differences with regard to bond strength and thus the magnitude of inhibition of a particular MMP do exist. 

Matrix Metalloproteinases. Table 1 MMPs and their genes known so far... 

Matrix Metalloproteinases. Figure 1 Domain organization of different mammalian MMPs. 

Matrix Metalloproteinases. Figure 2 ProMMP-2-TIMP-2 structure (adopted from [4]). TIMP-2 cartoon and transparent surface structure is shown in blue, MMP-2 in red. The C-terminal ends of both molecules are marked as spheres. 

Somerville RP, Oblander SA, Apte SS (2003) Matrix metalloproteinases old dogs with new tricks. Genome Biol 4 216... 

Stetler-Stevenson WG (1999) Matrix metalloproteinases in angiogenesis a moving target for therapeutic intervention. J Clin Invest 103 1237-1241... 

Morgunova E, Tuuttila A, Bergmann U et al (2002) Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2. Proc Natl Acad Sci USA 99 7414—7419... 

Metalloproteinases are a subgroup of proteinases. They are responsible for the cleavage of peptide bonds within a protein (proteolysis). Metalloproteinases contain a metal ion in the active center and are divided into four subclasses dependent on their mechanism of catalysis. 

The matrix metalloproteinases are inhibited by specific endogenous tissue inhibitor of metalloproteinases (TIMPs), which comprise a family of four protease inhibitors TIMP-1, TIMP-2, TIMP-3, and TIMP-4. Overall, all MMPs are inhibited by TIMPs once they are activated but the gelatinases (MMP-2 and MMP-9) can form complexes with TIMPs when the enzymes are in the latent form. 

Prenzel N, Zwick E, Daub H et al (1999) EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 402 884-888... 

Matrix Metalloproteinases Matrix-assisted Laser Desorption/Ionization Mass Spectrometry... 

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