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991.
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 P1′ and also accepts Val, Gly, and Pro at this position, whereas Ala is not preferred at P1′. Analysis by molecular modeling revealed that not only the size of the amino acid residue in P1′ but also the orientation of the neighboring P1 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. 相似文献
992.
Deoxyribonucleoside kinases(d NKs) phosphorylate deoxyribonucleosides to their corresponding monophosphate compounds. d Nks also phosphorylate deoxyribonucleoside analogues that are used in the treatment of cancer or viral infections. The study of the mammalian d NKs has therefore always been of great medical interest. However, during the last 20 years, research on d NKs has gone into nonmammalian organisms. In this review, we focus on non-viral d NKs, in particular their diversity and their practical applications. The diversity of this enzyme family in different organisms has proven to be valuable in studying the evolution of enzymes. Some of these newly discovered enzymes have been useful in numerous practical applications in medicine and biotechnology, and have contributed to our understanding of the structural basis of nucleoside and nucleoside analogue activation. 相似文献
993.
994.
Henriette Franz Kerstin Mosch Szabolcs Soeroes Henning Urlaub Wolfgang Fischle 《The Journal of biological chemistry》2009,284(50):35049-35059
Proteins containing defined recognition modules mediate readout and translation of histone modifications. These factors are thought to initiate downstream signaling events regulating chromatin structure and function. We identified CDYL1 as an interaction partner of histone H3 trimethylated on lysine 9 (H3K9me3). CDYL1 belongs to a family of chromodomain factors found in vertebrates. We show that three different splicing variants of CDYL1, a, b, and c, are differentially expressed in various tissues with CDYL1b being the most abundant variant. Although all three splicing variants share a common C-terminal enoyl-CoA hydratase-like domain, only CDYL1b contains a functional chromodomain implicated in H3K9me3 binding. A splicing event introducing an N-terminal extension right at the beginning of the chromodomain of CDYL1a inactivates its chromodomain. CDYL1c does not contain a chromodomain at all. Although CDYL1b displays binding affinity to methyl-lysine residues in different sequence context similar to chromodomains in other chromatin factors, we demonstrate that the CDYL1b chromodomain/H3K9me3 interaction is necessary but not sufficient for association of the factor with heterochromatin. Indeed, multimerization of the protein via the enoyl-CoA hydratase-like domain is essential for H3K9me3 chromatin binding in vitro and heterochromatin localization in vivo. In agreement, overexpression of CDYL1c that can multimerize, but does not interact with H3K9me3 can displace CDYL1b from heterochromatin. Our results imply that multimeric binding to H3K9me3 by CDYL1b homomeric complexes is essential for efficient chromatin targeting. We suggest that similar multivalent binding stably anchors other histone modification binding factors on their target chromatin regions. 相似文献
995.
Heiko Kroth Annalisa Ansaloni Yvan Varisco Asad Jan Nampally Sreenivasachary Nasrollah Rezaei-Ghaleh Valérie Giriens Sophie Lohmann María Pilar López-Deber Oskar Adolfsson Maria Pihlgren Paolo Paganetti Wolfgang Froestl Luitgard Nagel-Steger Dieter Willbold Thomas Schrader Markus Zweckstetter Andrea Pfeifer Hilal A. Lashuel Andreas Muhs 《The Journal of biological chemistry》2012,287(41):34786-34800
Increasing evidence implicates Aβ peptides self-assembly and fibril formation as crucial events in the pathogenesis of Alzheimer disease. Thus, inhibiting Aβ aggregation, among others, has emerged as a potential therapeutic intervention for this disorder. Herein, we employed 3-aminopyrazole as a key fragment in our design of non-dye compounds capable of interacting with Aβ42 via a donor-acceptor-donor hydrogen bond pattern complementary to that of the β-sheet conformation of Aβ42. The initial design of the compounds was based on connecting two 3-aminopyrazole moieties via a linker to identify suitable scaffold molecules. Additional aryl substitutions on the two 3-aminopyrazole moieties were also explored to enhance π-π stacking/hydrophobic interactions with amino acids of Aβ42. The efficacy of these compounds on inhibiting Aβ fibril formation and toxicity in vitro was assessed using a combination of biophysical techniques and viability assays. Using structure activity relationship data from the in vitro assays, we identified compounds capable of preventing pathological self-assembly of Aβ42 leading to decreased cell toxicity. 相似文献
996.
Martin Schwaiblmair Christian Faul Wolfgang von Scheidt Thomas M Berghaus 《Respiratory research》2012,13(1):18
Background
As differences in gas exchange between pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) have been demonstrated, we asked if cardiac output measurements determined by acetylene (C2H2) uptake significantly differed in these diseases when compared to the thermodilution technique.Method
Single-breath open-circuit C2H2 uptake, thermodilution, and cardiopulmonary exercise testing were performed in 72 PAH and 32 CTEPH patients.Results
In PAH patients the results for cardiac output obtained by the two methods showed an acceptable agreement with a mean difference of -0.16 L/min (95% CI -2.64 to 2.32 L/min). In contrast, the agreement was poorer in the CTEPH group with the difference being -0.56 L/min (95% CI -4.96 to 3.84 L/min). Functional dead space ventilation (44.5 ± 1.6 vs. 32.2 ± 1.4%, p < 0.001) and the mean arterial to end-tidal CO2 gradient (9.9 ± 0.8 vs. 4.1 ± 0.5 mmHg, p < 0.001) were significantly elevated among CTEPH patients.Conclusion
Cardiac output evaluation by the C2H2 technique should be interpreted with caution in CTEPH, as ventilation to perfusion mismatching might be more relevant than in PAH. 相似文献997.
Albrecht Guhlmann Wolfgang Hagmann Dietrich Keppler 《Prostaglandins & other lipid mediators》1987,34(1)
N-Acetyl-leukotriene E4, the end product of leukotriene C4 metabolism in the mercapturic acid pathway, was rapidly eliminated from the blood circulation into the bile of rats. Part of the N-acethyl-leukotriene E4 secreted from bile into the intestine undewent enterohepatic circulation. Leukotriene absorption occurred from the small intestine and from the colon. Biliary and urinary excretion within 5.5 h amounted to 15 and 2%, respectively, of the intraduodenally administered N-acetyl- H leukotriene E4 in animals anesthetized with ketamine. HPLC analyses indicated that 35% of the biliary radioactivity corresponded to unchanged N-acetyl- H leukotriene E4, while 65% in bile and 100% in urine were polar metabolites. Enterohepatic circulation extends the biological half-life of N-acetyl-leukotriene E4. 相似文献
998.
The obstructive sleep apnea syndrome is a disorder of sleep and breathing that is being recognized with increasing frequency. The pathophysiologic consequences range from mild sleepiness to life-threatening cardiovascular and respiratory decompensation. The primary forms of treatment are directed at modifying the upper airway with either an operation or continuous positive airway pressure. Aside from tracheostomy, which is virtually always successful, other forms of treatment have met with varying results. Ancillary therapy, including oxygen, weight loss and drugs, is often helpful but seldom curative. Follow-up sleep studies are necessary to evaluate the effectiveness of treatment. Selecting therapy for a patient with obstructive sleep apnea requires a comprehensive evaluation including polysomnography, special examinations of the upper airway and assessing the cardiopulmonary status. Therapy is based on the severity of disease and must be tailored to each patient. 相似文献
999.
Cytochalasin B (CB) is known to interfere reversibly with the cytoplasmic contractile filamental network of mammalian cells. The role of the microfilament system in the mechanism of the reactive oxygen intermediates release of polymorphonuclear leukocytes (PMNL) was studied for different kinds of stimuli. PMNL from fresh human blood were treated with CB and stimulated by adherence on plastic surfaces, by opsonized zymosan, by phorbol myristate acetate and by N-formylmethionyl-phenylalaline. The production of reactive oxygen species were monitored by simultaneous detection of native, luminol-independent, luminescence (NL) and luminol-dependent luminescence (LDL) using a method of spectral discrimination. Different influences of CB on NL with respect to LDL as well stimuli-dependent influences of CB on the luminescence response of PMNL were observed. Especially phagocytosis-associated activation of PMNL was strongly inhibited by CB, whereas LDL was reduced to a much greater extent in comparison with NL. A firm involvement of the microfilament system is indicated, but it depends on the kind of stimulus engaged. 相似文献
1000.