Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mononuclear phagocytes have the capacity to produce an array of MMPs. Several of these proteinases are capable of degrading insoluble elastin, an important component for the structural stability of the lung. Matrilysin is a low molecular weight proteinase with a broad substrate specificity produced at highest levels in in vitro differentiated monocytes. The 92-kD gelatinase is a major product of human alveolar macrophages that is also an elastase. The most newly described member of the MMP family is human macrophage metalloelastase. This enzyme is also expressed in alveolar macrophages derived from cigarette smokers. Determining the contribution of these and other elastolytic proteinases to the pathogenesis of emphysema is a focus of ongoing research.
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PMID:Elastolytic metalloproteinases produced by human mononuclear phagocytes. Potential roles in destructive lung disease. 795 53

The matrix metalloproteinases (MMP) are a multigenic family involving 14 enzymes which can cleave most, if not all, the components of the extracellular matrix (interstitium and basement membranes). The present work reports on the main structural characteristics, the substrate preference and the site synthesis of these proteinases and their inhibitors (TIMP). Human MMPs are produced by various cell types and are involved in the remodelling of the extracellular matrix in many physiological and pathophysiological circumstances. Elastolytic MMPs produced by monocytes and/or macrophages (matrilysin, gelatinases, macrophage elastase) are likely to be implicated in the development of acquired pulmonary emphysema.
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PMID:[Metalloproteinases in the extracellular matrix: structure and activity]. 908

The macrophage elastase enzyme (MMP-12) expressed mainly in alveolar macrophages has been identified in the mouse lung as the main destructive agent associated with cigarette smoking, which gives rise to emphysema, both directly via elastin degradation and indirectly by disturbing the proteinase/antiproteinase balance via inactivation of the alpha1-proteinase inhibitor (alpha1-PI), the antagonist of the leukocyte elastase. The catalytic domain of human recombinant MMP-12 has been crystallized in complex with the broad-specificity inhibitor batimastat (BB-94). The crystal structure analysis of this complex, determined using X-ray data to 1.1 A and refined to an R-value of 0.165, reveals an overall fold similar to that of other MMPs. However, the S-shaped double loop connecting strands III and IV is fixed closer to the beta-sheet and projects its His172 side-chain further into the rather hydrophobic active-site cleft, defining the S3 and the S1-pockets and separating them from each other to a larger extent than is observed in other MMPs. The S2-site is planar, while the characteristic S1'-subsite is a continuous tube rather than a pocket, in which the MMP-12-specific Thr215 replaces a Val residue otherwise highly conserved in almost all other MMPs. This alteration might allow MMP-12 to accept P1' Arg residues, making it unique among MMPs. The active-site cleft of MMP-12 is well equipped to bind and efficiently cleave the AlaMetPhe-LeuGluAla sequence in the reactive-site loop of alpha1-PI, as occurs experimentally. Similarities in contouring and particularly a common surface hydrophobicity both inside and distant from the active-site cleft explain why MMP-12 shares many substrates with matrilysin (MMP-7). The MMP-12 structure is an excellent template for the structure-based design of specific inhibitors for emphysema therapy and for the construction of mutants to clarify the role of this MMP.
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PMID:Substrate specificity determinants of human macrophage elastase (MMP-12) based on the 1.1 A crystal structure. 1157 28

Human matrilysin-1 (MMP-7) is one of the most potent elastases besides macrophage elastase in the family of matrix metalloproteinases (MMPs). It has been reported to provide macrophages with the highest elastinolytic capacity and plays key roles in diseases such as emphysema and cancer. Describing the enzymatic turnover of matrix components helps to understand the molecular basis of disease processes. Hence, in this work, the cleavage behavior of MMP-7 with respect to its natural substrate human elastin was investigated using mass spectrometric (MS) techniques and molecular modeling. Elastin peptides in the range of 500-8000 Da released through the action of MMP-7 were analyzed and domains susceptible to proteolytic attack by MMP-7 were identified. MMP-7 was found to mainly cleave in N- and C-terminal regions of elastin's precursor, which involves linkages in domains encoded by exons 2, 3, 5-7, 26, and 30-33. In contrast, only few cleavages were found in the central part of the precursor and no cleavages in regions in elastin that are involved in cross-linking. MMP-7 shows a strong preference for Leu in P(1)' and also accepts Val, Gly, and Pro at this position, whereas Ala is not preferred at P(1)'. Analysis by molecular modeling revealed that not only the size of the amino acid residue in P(1)' but also the orientation of the neighboring P(1) residue and, thus, the orientation of the peptide bond that is cleaved influences the cleavage preference of MMP-7. Overall, this study provides an important insight into the degradation of human elastin by MMP-7 and may aid in the development of approaches to treat elastin-degrading diseases.
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PMID:Insights into the degradation of human elastin by matrilysin-1. 2088 20