Matrix metalloproteinase stromelysin

A. Lochter, S. Galosy, J. Muschler, N. Freedman, Z. Werb, and M. J. Bissell. Matrix metalloproteinase stromelysin-1 tri ers a cascade of molecular alterations that leads to stable epithelial-to-mesenclymal conversion and a prema%nant phenotype in mammary epithelial cells. J CeU Biol, 139 (7), 1861-1872, 1997. 

Shi Y-B, Fu L, Hasebe T, Ishizuya-Oka A (2007) Regulation of extracellular matrix remodeling and cell fate determination by matrix metalloproteinase stromelysin-3 during thyroid hormone-dependent post-embryonic development. Pharmacol Therapeut 116(3 ) 391-400. doi 10.1016/j. pharmthera.2007.07.005... 

Ramos-DeSimone N, Hahn-Dantona E, Sipley J et al (1999) Activation of matrix metalloproteinase-9 (MMP-9) via a converging plasmin/stromelysin-1 cascade enhances tumor cell invasion. J Biol Chem 274 13066-13076... 

Dunten, P, Kammlott, U., Crowther, R., et al. (2001) X-ray structure of a novel matrix metalloproteinase inhibitor complexed to stromelysin. Protein Science, 10, 923-926. 

One of the earliest examples of FBDD was on the protein stromelysin, or matrix metalloproteinase 3 (MMP-3), which is implicated in arthritis and tumor metastasis. This was tackled by researchers at Abbott Laboratories using SAR by NMR. A previous high-throughput screen of 115,000 compounds had failed to identify any hits with potencies better than 10 pM. 

Matrix metalloproteinases (MMPs) are a family of enzymes that degrade constituents of the extracellular matrix and the basement membrane. They include collagenases, gelatinases, stromelysins and membrane type MMPs. 

Figure 6.19 values of fragments tested for their ability to chelate the active site zinc in stromelysin as determined by NMR. (Hajduk, PJ. et al. NMR-based modification of matrix metalloproteinase inhibitors with improved bioavailability. J. Med. Chem. 2002, 45, 5628-5639.)... 

M4. Manicourt, D. H., Fujimoto, N., Obata, K., and Thonar, E. J., Levels of circulating collagenase, stromelysin-1, and tissue inhibitor of matrix metalloproteinases 1 in patients with rheumatoid arthritis. Relationship to serum levels of antigenic keratan sulfate and systemic parameters of inflammation. Arthritis Rheum. 38, 1031-1039... 

Obata, K., Iwata, K., Okada, Y., et al., A one-step sandwich enzyme immunoassay for human matrix metalloproteinase 3 (stromelysin-1) using monoclonal antibodies. Clin. Chim. Acta 211, 59-72 (1992). 

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. 

---