Matrix Metalloproteinases, enzymes

To further extend the utility of structural methods, researchers compare solid state X-ray crystallographic and solution-state NMR structures to define important differences. For instance, the Bertini group has studied the enzyme matrix metalloproteinase 12 (MMP12), in the presence of its inhibitors. Matrix metalloproteinases (MMPs) are involved in extracellular matrix degradation, a fundamental step in tissue remodeling and repair. There are a great variety of enzymes of this type, the one studied here is one of many found in humans. Most MMPs have three domains (1) a prodomain that is removed... 

The crude organic extracts of a Penicillium sp. isolated from a depth of 885 ft. were active against Staphylococcus aureus and in the brine shrimp lethality screen. These extracts were further tested using enzyme inhibition assays for two different signal transduction enzymes - matrix metalloproteinase-3 (MMP-3) and caspase-1 (Casp-1). Compounds 13 and 14 were isolated from the chloroform extracts of the broth filtrate of a Penicillium sp. found growing in Berkeley Pit Lake. Berkeleydione (13, 5.5 mg/L) was isolated as a crystalline... 

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. 

Gelman BB, Wolf DA, Rodriguez-Wolf M et al (1997) Mononuclear phagocyte hydrolytic enzyme activity associated with cerebral HIV-1 infection. Am J Pathol 151 1437-1446 Giraudon P, Buart S, Bernard A et al (1997) Cytokines secreted by gUal cells infected with HTLV-I modulate the expression of matrix metalloproteinases (MMPs) and their natural inhibitor (TIMPs) possible involvement in neurodegenerative processes. Mol Psychiatry 2(107-10) 84... 

Increased levels of protease enzymes such as matrix metalloproteinases... 

Matrix metalloproteinases Zinc-dependent enzymes capable of degrading extracellular matrix proteins, including connective tissue. 

Arylmethyl-9-hydroxypyrazino[l,2-f]pyrimidine-l,8-dione derivatives have been claimed as anti-HIV agents <2005W02005/016927, 2005W02005/087766> 6,8-dioxo-pyrazino[l,2-f]pyrimidine-3-carboxamides 164 (Y = NH) <2004W02004/014354> and their saturated analogues <2004USP2004/034009> have been claimed as matrix metalloproteinase MMP-13 enzyme inhibitors, useful in the treatment of rheumatoid arthritis. 

The 3-carboxamido derivatives of pyrimido[6,l-c][l,4]oxazine-6,8-diones 164 (Y = 0), as with their nitrogen and sulfur-containing analogues, are matrix metalloproteinase inhibitors useful for treating MMP-13 enzyme-mediated diseases (e.g., heart failure, multiple sclerosis, and macular degeneration) <2004W02004/014354>. 

The hypothesis that stress can modulate MMP expression is also supported by studies in mice. Using social isolation as a stressor, the mRNA levels of MMP-2, MMP-9, matrix-type matrix metalloproteinase-1 (MT1-MMP), and urokinase-type plasminogen activator were higher in the tumor and liver tissues of the isolated mice than in control mice.91 Furthermore, a recent study has shown that restraint stress causes an increase in expression of the plasminogen activator inhibitor-1, another key player in the plas-minogen/plasmin enzyme system in mice.92 As these enzymes have been described to have functions besides their role in ECM remodeling,93 studies on stress-related effects on MMP/TIMP balance have implications in the relationship between stress and cancer initiation and progression.. 

Matrix metalloproteinases (MMPs) are a class of zinc- and calcium-dependent enzymes that are responsible for the metabolism of extracellular matrix proteins [27]. Increased activity of MMPs has been associated with pathological diseases such as arthritis, cancer, multiple sclerosis and Alzheimer s disease [28-31]. Therefore, they constitute an important group of drug targets. Their inhibition is accomplished by blocking the active site of the catalytic domain with ligands that contain hydroxamic or carboxylic acids to chelate the Zn metal. The identification of low molecular weight compounds that contain different scaffolds may lead to the development of a new class of specific inhibitors. 

Trispyrazolylborates are models for tris-histidine active sites in zinc enzymes, e.g., the matrix metalloproteinases involved in breakdown of extracellular matrices. Inhibition of these metalloproteinases may prove valuable in the treatment of, inter alios, cancer and arthritis, so efforts are being made to find appropriate ligands to block the zinc active site. The search has recently moved on from hydroxamates to hydroxypyridinones - l-hydroxy-2-pyridinone is a cyclic analogue of hydroxamic acid. As reported in Section II.B.2 earlier, hydroxypyridinones form stable five-coordinate complexes on reaction with hydrotris(3,5-phenylmethylpyrazolyl)borate zinc hydroxide. Modeling studies suggest that hydroxypyridinonate ligands should be able to access the active site in the enzyme with ease (110). 

In a study conducted by Szardenings et various combinatorial libraries of DPKs scaffolds were created to design and evaluate the activity of DPKs as inhibitors of the matrix metalloproteinases, namely, collegenase-1 and gelatinase B. This study created structure-activity relationships (SAR) for side chains attached to a DPK core structure. These enzymes are therapeutic targets with indications in the treatment of cancer, arthritis, autoimmunity, and cardiovascular disease. 

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