Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activation of procollagenase and prostromelysin by mechanisms that might be functional in vivo has been investigated. Studies with cell monolayers plated onto collagen films have indicated key roles for plasmin and TIMP in these processes. Prostromelysin activation could be rapidly effected by fibroblast monolayers in the presence of plasminogen, with identical kinetics to plasminogen-streptokinase generated plasmin. Procollagenase activation by plasmin was shown to be poor, although an M(r) shift of 11,000 occurred. Activation was enhanced ten-fold by the presence of active stromelysin even at a very low molar ratio. A tumour cell line secreting procollagenase but not stromelysin was found to be dependent upon the addition of both stromelysin and plasminogen to effect degradation of collagen films. Biochemical studies of metalloproteinase activation were carried out using other purified proteinases synthesized by connective tissue cells including endopeptidase 24.11, endopeptidase-2, cathepsin B and cathepsin L. None was a particularly effective activator relative to plasmin, but cathepsin B was shown to activate stromelysin. By use of both cell model systems and biochemical studies of purified enzymes we have found that the role of plasmin as the major metalloproteinase activator in normal connective tissue cells remains unchallenged.
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PMID:Physiological mechanisms for metalloproteinase activation. 148 31

A three-dimensional model of the 507-749 region of neutral endopeptidase-24.11 (NEP; E.C.3.4.24.11) was constructed integrating the results of secondary structure predictions and sequence homologies with the bacterial endopeptidase thermolysin. Additional data were extracted from the structure of two other metalloproteases, astacin and stromelysin. The resulting model accounts for the main biological properties of NEP and has been used to describe the environment close to the zinc atom defining the catalytic site. The analysis of several thiol inhibitors, complexed in the model active site, revealed the presence of a large hydrophobic pocket at the S1' subsite level. This is supported by the nature of the constitutive amino acids. The computed energies of bound inhibitors correspond with the relative affinities of the stereoisomers of benzofused macrocycle derivatives of thiorphan. The model could be used to facilitate the design of new NEP inhibitors, as illustrated in the paper.
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PMID:A three-dimensional construction of the active site (region 507-749) of human neutral endopeptidase (EC.3.4.24.11). 1019 85

The common acute lymphoblastic leukemia antigen (neprilysin, CD10, neutral endopeptidase 24.11) is a member of the neprilysin family, and projects functions in signaling pathways in pathophysiological processes such as cancer, Alzheimer's disease and hypertension. Given its pathophysiological importance, an investigation of the natural substrate specificity of this metalloprotease is presented here through the application of enzyme-substrate modeling and molecular dynamics simulations. The results show that the substrate modeled, LATAC downward arrow FG, satisfies a complementary backbone H-bonding with Ala543-Tyr545, thereby suggested to be the putative substrate-binding beta-sheet, analogously to matrix metalloproteases. The modeling further suggests that phenylalanine at the P1' position (substrate) is directed in the same fashion as the synthetic inhibitor of the reference crystal structure and that this enzyme does not bind the P3'/P4' positions of a substrate, as other metalloproteases do. After a specific comparison with one member of the matrix metalloproteases, MMP-3, a common conserved valine residue at the primary S1' subsite was found to be shared between these two otherwise different proteases. These results may prove useful for selective drug design for neprilysin, and lay a foundation for future subsite analysis for other members of the neprilysin family.
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PMID:Computer modeling and nanosecond simulation of the enzyme-substrate complex of the common lymphoblastic leukemia antigen (neprilysin) indicates shared residues at the primary specificity pocket (S1') with matrix metalloproteases. 1451 14