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)

The Mmineral springs alpha 1-antitrypsin (alpha 1AT) allele, causing alpha 1AT deficiency and emphysema, is unique among the alpha 1AT-deficiency alleles in that it was observed in a black family, whereas most mutations causing alpha 1AT deficiency are confined to Caucasian populations of European descent. Immobilized pH gradient analysis of serum demonstrated that alpha 1AT Mmineral springs migrated cathodal to the normal M2 allele. Evaluation of Mmineral springs alpha 1AT as an inhibitor of neutrophil elastase, its natural substrate, demonstrated markedly lower than normal function. Characterization of the alpha 1AT Mmineral springs gene demonstrated that it differed from the common normal M1(Ala213) allele by a single-base substitution causing the amino acid substitution Gly-67 (GGG)----Glu-67 (GAG). Capitalizing on the fact that this mutation creates a polymorphism for the restriction endonuclease AvaII, family analysis demonstrated that the Mmineral springs alpha 1AT allele was transmitted in an autosomal-codominant fashion. Evaluation of genomic DNA showed that the index case was homozygous for the alpha 1AT Mmineral springs allele. Cytoplasmic blot analysis of blood monocytes of the Mmineral springs homozygote demonstrated levels of alpha 1AT mRNA transcripts comparable to those in cells of a normal M1 (Val213) homozygote control. Evaluation of in vitro translation of Mmineral springs alpha 1AT mRNA transcripts demonstrated a normal capacity to direct the translation of alpha 1AT. Evaluation of secretion of alpha 1AT by the blood monocytes by pulse-chase labeling with [35S]methionine, however, demonstrated less secretion by the Mmineral springs cells than normal cells. To characterize the posttranslational events causing the alpha 1AT-secretory defect associated with the alpha 1AT Mmineral springs gene, retroviral gene transfer was used to establish polyclonal populations of murine fibroblasts containing either a normal human M1 alpha 1AT cDNA or an Mmineral springs alpha 1AT cDNA and expressing comparable levels of human alpha 1AT mRNA transcripts. Pulse-chase labeling of these cells with [35S]methionine demonstrated less secretion of human alpha 1AT from the Mmineral springs cells than from the M1 cells, and evaluation of cell lysates also demonstrated lower amounts of intracellular human alpha 1AT in the Mmineral springs cells than in the normal M1 control cells. Thus, the Gly-67 --> Glu mutation that characterizes Mmineral springs causes reduced alpha 1AT secretion on the basis of aberrant posttranslational alpha 1AT biosynthesis by a mechanism distinct from that associated with the alpha 1AT Z allele, whereby intracellular aggregation of the mutant protein is etiologic of the alpha 1AT-secretory defect. Furthermore, for the alpha 1AT protein that does reach the circulation, this mutation markedly affects the ability of the molecule to inhibit neutrophil elastase; i.e., the alpha 1AT Mmineral springs allele predisposes to emphysema on the basis of serum apha 1AT deficiency coupled with alpha AT dysfunction.
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PMID:Molecular basis of alpha 1-antitrypsin deficiency and emphysema associated with the alpha 1-antitrypsin Mmineral springs allele. 196 87

Proteinase 3 is a human polymorphonuclear leukocyte serine proteinase that degrades elastin in vitro and causes emphysema when administered by intratracheal insufflation into hamsters. Proteinase 3, stored in the azurophilic granules, is expressed in progenitor cells of myeloid origin. In the present study, the biosynthesis, processing, and intracellular transport of the enzyme was investigated in the human myelomonocytic cell line U937. Proteinase 3 is initially identified as a 35-kDa precursor and converted into the 29-kDa mature form within 3 h. By using a combination of techniques including amino-terminal sequencing, we identified the 35-kDa form as a zymogen containing an activation dipeptide but lacking the amino-terminal 25 residues, presumably the result of cleavage by a signal peptidase. Tunicamycin treatment and alkalinization of acidic cell compartments with NH4Cl did not prevent the processing of the proteinase 3 zymogen into the mature form, suggesting that the enzyme is targeted to the cytoplasmic granules by a mechanism other than the mannose 6-phosphate receptor. Brefeldin A inhibited the zymogen processing, suggesting that the dipeptide cleavage occurred in a post-Golgi organelle. The enzyme responsible for the removal of the dipeptide is a cysteine proteinase since E-64d, a class-specific inhibitor, prevented processing. However, treatment of cells with a dipeptidyl peptidase I inhibitor, Gly-Phe-diazomethyl ketone and with the lysosomotropic agents, NH4Cl and chloroquine, did not prevent dipeptide cleavage, indicating that the processing enzyme for proteinase 3 is not dipeptidyl peptidase I. In contrast, Gly-Phe-diazomethyl ketone inhibited cleavage of the dipeptide from cathepsin G. This indicates that processing of proteinase 3 is distinct from that of cathepsin G. Proteinase 3 is also processed at the COOH-terminal extension. Cleavage takes place next to Arg-222, suggesting that a trypsin-like proteinase is involved in the COOH-terminal processing.
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PMID:Biosynthesis and processing of proteinase 3 in U937 cells. Processing pathways are distinct from those of cathepsin G. 862 89

Human neutrophil elastase (HNE, IEC 3. 4. 21. 37) is a causative factor of inflammatory diseases, including emphysema and rheumatoid arthritis. Enzymatic characterization is important for the development of new drugs involved in the regulation of this enzyme. In this study, we investigated the enzymatic and biochemical properties of five different elastolytic enzymes, with a molecular mass between 24 kDa and 72 kDa. Three elastases, molecular masses of 27, 29, 31 kDa, might be elastase isozymes that have the same NH2-terminal amino acid sequences of Ile-Val-Gly-Gly-Arg-Arg-Ala. The 24-kDa enzyme, which showed the identical NH2-terminal amino acid sequences to elastase, was a degraded fragment of native elastase. The elastolytic activity was conserved at the 6/7 domain of the NH2-terminal region. The inhibitory characteristics of PMSF, DipF were the same as those of native elastases. The 72-kDa molecule, which showed elastolytic activity, might be a trimer formed between native elastases (31 kDa and 29 kDa) and a cathepsin G-like enzyme, which did not show elastolytic activity but enhanced the elastolytic activity of neutrophil elastase. Although this cathepsin G-like enzyme showed weak cathepsin G activity, it has distinguishable NH2-terminal sequences of Ile-Val-Gly-Gly-Ser-Arg-Ala- from those of elastase or cathepsin G. The potentiation of elastolytic activity could be a result of the trimerization of native elastase with a cathepsin G-like enzyme, and was then weakly inhibited by serine protease inhibitors, such as PMSF, DipF. Therefore, we suggest the cathepsin G-like enzyme to be a novel enzyme, which has an important role in the development of inflammation.
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PMID:Enzymatic and molecular biochemical characterizations of human neutrophil elastases and a cathepsin G-like enzyme. 1110 Nov 39

The Z variant of alpha1-antitrypsin (Z-AT) is present in 4% of Northern Europeans and is associated with liver cirrhosis and emphysema. Polymers accumulate within the hepatocyte and the subsequent plasma deficiency of AT renders the lungs susceptible to proteolysis and early onset emphysema. We have previously demonstrated that the Phe-Leu-Glu-Ala-Ile-Gly (6 mer) peptide specifically binds to Z-AT and inhibits polymerization. Here we present the first detailed biochemical study of the purified Z-AT-6 mer binary complex. Biochemical studies indicated that this complex was inactive as a proteinase inhibitor and the peptide annealed to beta-sheet A of Z-AT. Removal of the N-acetyl terminus of the 6 mer peptide did not affect the peptide's ability to prevent polymer formation. However, the nonacetylated 6 mer-Z-AT complex dissociated at a rate 2.75 x faster than the acetylated 6 mer-Z-AT complex to yield an active inhibitor; Koff 5.5 +/- 1.07 versus 2.0 +/- 0.25 10(6) s(-1), respectively. These biochemical data indicate a potential therapeutic approach whereby polymerization is prevented in the liver, with the gradual release of the peptide from the binary complex restoring proteinase inhibitory function within the tissues. Thus, it raises the novel prospect of ameliorating both the cirrhosis and the emphysema associated with Z-AT.
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PMID:Inhibiting polymerization: new therapeutic strategies for Z alpha1-antitrypsin-related emphysema. 1501 19

Elastin, one of the extracellular matrix components, is present in tissues requiring extensibility and resilience such as the aorta, lungs, ligaments and skin. Degradation of elastin is observed in diseases such as atherosclerosis, emphysema and metastasis. It has been suggested that degraded elastin-derived peptides interact with a variety of cell types and are involved in development of diseases. Two nonapeptides, Ala-Gly-Val-Pro-Gly-Leu-Gly-Val-Gly (AGVPGFGVG) and Ala-Gly-Val-Pro-Gly-Phe-Gly-Val-Gly (AGVPGFGVG), exist in hydrophobic regions of elastin. In this paper, we characterized these elastin-derived nonapeptides by macrophage migration assay. Both nonapeptides induced a maximal migration at 10(-8) M and elicited the same degree of responsiveness. To investigate the role of the sixth residue of the nonapeptides, seven analog peptides in which Leu or Phe is substituted by Ile, Val, Ala, Gly, Pro, Lys or Glu were synthesized and their macrophage migration activity tested. Among the nonapeptide analogs, only Ala-Gly-Val-Pro-Gly-Ile-Gly-Val-Gly induced the migration of macrophages at the optimal concentration of 10(-9) M and its responsiveness was the same as that of parent nonapeptide AGVPGFGVG. Results of the deactivation tests and the effect of lactose on macrophage migration showed that a lactose-insensitive receptor which mainly recognizes Ala-Gly-Val-Pro-Gly-Ile-Gly-Val-Gly is presumably present on the membrane of macrophages in addition to the elastin-binding protein (EBP) sensitive to lactose. These results suggest that Leu, Phe and Ile residues at the sixth position of elastin-derived nonapeptides are crucial for inducing macrophage migration and in particular, Ile residue is important for the recognition by receptor insensitive to lactose.
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PMID:Induction of macrophage migration through lactose-insensitive receptor by elastin-derived nonapeptides and their analog. 1739 24

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

Chronic obstructive pulmonary disease (COPD), characterized by intermittent exacerbations and clinical subphenotypes like emphysema and chronic bronchitis, poses a significant risk of lung cancer (LC) development. Metabolomic studies of COPD are scarce, and those of LC patients with COPD subphenotypes have not been investigated. To study metabolite profile alteration in LC patients with different COPD subphenotypes, lung paracancer tissue from 10 LC (CON) patients, 10 LC patients with emphysema (E), and 9 LC patients with chronic bronchitis (CB) were analyzed using gas chromatography-mass spectrometry. Multivariate analysis indicated a distinct separation between LC patients with COPD subphenotypes and LC patients. Overall, 60, 55, 33 and 63 differential metabolites (DM) were identified in comparisons between CB vs CON, E vs CON, CB vs E, and CB + E vs CON, respectively, and of these, 8 DM were shared in all comparisons. Among the high altered metabolites, E samples showed higher 'acetol' than CON samples, and lower 'azelaic acid', '3-methylglutaric acid' and 'allose'. CB samples showed higher 'turanose' and 'o-phosphoserine' and lower 'anandamide' than CON and E samples. In CB and E samples, 'galactonic acid', '2-mercaptoethanesulfonic acid', 'D-alanyl-D-alanine' '3-methylglutaric acid', 'glycine', 'L-4-Hydroxyphenylglycine' and 'O-phosphonothreonine' had common alteration trends compared with those of CON samples. 'Glycine', 'L-4-Hydroxyphenylglycine' and 'O-phosphonothreonine' were significantly enriched in glycine, serine and threonine metabolism pathways. The total differential metabolites detected were remarkably altered in pyrimidine, beta-alanine and purine metabolism. Our study provided altered DM patterns of lung paracancer tissue, the key metabolites and their enriched metabolic pathways in LC patients with different COPD subphenotypes.
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PMID:Metabolomic analysis of lung cancer patients with chronic obstructive pulmonary disease using gas chromatography-mass spectrometry. 3279 77