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991.
Brunetti L Galeazzi R Orena M Bottoni A 《Journal of molecular graphics & modelling》2008,26(7):1082-1090
Peptidoglycan, a key constituent of bacterial cell walls, is currently the target of broad spectrum antibiotics and a new research field involves both design and synthesis of inhibitors of its biosynthesis. Most bacteria require either lysine, or its biosynthetic precursor, diaminopimelate (meso-DAP), as a component of the peptidoglycan layer of the cell wall. In this paper, molecular modelling studies were undertaken in order to shed light on the molecular basis of interaction between (2S,6S)-diaminopimelic acid (l,l-DAP) (1) with its target enzyme DAP-epimerase, since this is a key step in the lysine biosynthetic path leading to (2R,6S)-diaminopimelic acid (meso-DAP) (2). In particular, the docking of the ligand-enzyme complex was studied by means of MD simulations and DFT computations in order to ascertain the optimal structural requirements for the epimerization reaction. Molecular dynamics simulations clearly showed that the configuration of the distal carbon C6 of l,l-DAP is critical for complex formation since both amino and carboxylate groups are involved in Hbonding interactions with the active site residues. Furthermore, the interactions occurring between the functional groups bonded to the C2 and some residues of the binding cavity immobilize the ligand in a position appropriate for the epimerization reaction, i.e., exactly in the middle of the two catalytic residues Cys73 and Cys217 as confirmed by DFT quantum mechanical computation of the Michaelis complex. All this mechanistic information could be useful for the rational design of new potential antibiotic drugs effective as inhibitors of peptidoglycan biosynthesis. 相似文献
992.
Modeling and visualizing molecular surfaces is an important and challenging task in bioinformatics. Such surfaces play an essential role in better understanding the chemical and physical properties of molecules. However, constructing and displaying molecular surfaces requires complex algorithms. In this article we introduce MetaMol, a new program that generates high-quality images in interactive time. In contrast with existing software that discretizes the surface with triangles or grids, our program is based on a GPU accelerated ray-casting algorithm that directly uses the piecewise-defined algebraic equation of the molecular skin surface. As a result, both better performances and higher quality are obtained. 相似文献
993.
Intharathep P Laohpongspaisan C Rungrotmongkol T Loisruangsin A Malaisree M Decha P Aruksakunwong O Chuenpennit K Kaiyawet N Sompornpisut P Pianwanit S Hannongbua S 《Journal of molecular graphics & modelling》2008,27(3):342-348
To understand how antiviral drugs inhibit the replication of influenza A virus via the M2 ion channel, molecular dynamics simulations have been applied to the six possible protonation states of the M2 ion channel in free form and its complexes with two commercial drugs in a fully hydrated lipid bilayer. Among the six different states of free M2 tetramer, water density was present in the pore of the systems with mono-protonated, di-protonated at adjacent position, tri-protonated and tetra-protonated systems. In the presence of inhibitor, water density in the channel was considerably better reduced by rimantadine than amantadine, agreed well with the experimental IC(50) values. With the preferential position and orientation of the two drugs in all states, two mechanisms of action, where the drug binds to the opening pore and the histidine gate, were clearly explained, i.e., (i) inhibitor was detected to localize slightly closer to the histidine gate and can facilitate the orientation of His37 imidazole rings to lie in the close conformation and (ii) inhibitor acts as a blocker, binding at almost above the opening pore and interacts slightly with the three pore-lining residues, Leu26, Ala30 and Ser31. Here, the inhibitors were found to bind very weakly to the channel due to their allosteric hindrance while theirs side chains were strongly solvated. 相似文献
994.
The aim of this review is to provide an overview of proteomic studies in animal models of diabetes and to give some insight into the different methods available today in the rapidly developing field of proteomics. A summary of 31 papers published between 1997 and 2007 is presented. For instance, proteomics has been used to study the development of both type 1 and type 2 diabetes, diabetic complications in tissues like heart, kidney and retina and changes after treatment with anti-diabetic drugs like peroxisome proliferator-activated receptors agonists. Together, these studies give a good overview of a number of experimental approaches. Proteomics holds the promise of providing major contributions to the field of diabetes research. However, to achieve this, a number of issues need to be resolved. Appropriate data representation to facilitate data comparison, exchange, and verification is required, as well as improved statistical assessment of proteomic experiments. In addition, it is important to follow up the results with functional studies to be able to make biologically relevant conclusions. The potential of proteomics to dissect complex human disorders is now beginning to be realized. In the future, this will result in new important information concerning diabetes. 相似文献
995.
Lamarque M Tastet C Poncet J Demettre E Jouin P Vial H Dubremetz JF 《Proteomics. Clinical applications》2008,2(9):1361-1374
The Plasmodium falciparum food vacuole (FV) is a lysosome-like organelle where erythrocyte hemoglobin digestion occurs. It is a favorite target in the development of antimalarials. We have used a tandem mass spectrometry approach to investigate the proteome of an FV-enriched fraction and identified 116 proteins. The electron microscopy analysis and the Western blot data showed that the major component of the fraction was the FV and, as expected, the majority of previously known FV markers were recovered. Of particular interest, several proteins involved in vesicle-mediated trafficking were identified, which are likely to play a key role in FV biogenesis and/or FV protein trafficking. Recovery of parasite surface proteins lends support to the cytostomal pathway of hemoglobin ingestion as a FV trafficking route. We have identified 32 proteins described as hypothetical in the databases. This insight into FV protein content provides new clues towards understanding the biological function of this organelle in P. falciparum. 相似文献
996.
Nelsestuen GL Harvey SB Zhang Y Kasthuri RS Sinaiko AR Ely EW Bernard GR Homoncik M Jilma B 《Proteomics. Clinical applications》2008,2(2):158-166
Although numerous protein biomarkers have been correlated with advanced disease states, no new clinical assays have been developed. Goals often anticipate disease-specific protein changes that exceed values among healthy individuals, a property common to acute phase reactants. This review considers somewhat different approaches. It focuses on intact protein isoform ratios that present a biomarker without change in the total concentration of the protein. These will seldom be detected by peptide level analysis or by most antibody-based assays. For example, application of an inexpensive method to large sample groups resulted in observation of several polymorphisms, including the first structural polymorphism of apolipoprotein C1. Isoform distribution of this protein was altered and was eventually linked to increased obesity. Numerous other protein isoforms included C- and N-terminal proteolysis, changes of glycoisoform ratios and certain types of sulfhydryl oxidation. While many of these gave excellent statistical correlation with advanced disease, clinical utility was not apparent. More important may be that protein isoform ratios were very stable in each individual. Diagnosis by longitudinal analysis of the same individual might increase sensitivity of protein biomarkers by 20-fold or more. Protein changes that exceed the range of values found among healthy individuals may be uncommon. 相似文献
997.
Barelli S Canellini G Thadikkaran L Crettaz D Quadroni M Rossier JS Tissot JD Lion N 《Proteomics. Clinical applications》2008,2(2):142-157
Protein oxidation mechanisms result in a wide array of modifications, from backbone cleavage or protein crosslinking to more subtle modifications such as side chain oxidations. Protein oxidation occurs as part of normal regulatory processes, as a defence mechanism against oxidative stress, or as a deleterious processes when antioxidant defences are overcome. Because blood is continually exposed to reactive oxygen and nitrogen species, blood proteomics should inherently adopt redox proteomic strategies. In this review, we recall the biochemical basis of protein oxidation, review the proteomic methodologies applied to analyse redox modifications, and highlight some physiological and in vitro responses to oxidative stress of various blood components. 相似文献
998.
O'Riordan E Orlova TN Mendelev N Patschan D Kemp R Chander PN Hu R Hao G Gross SS Iozzo RV Delaney V Goligorsky MS 《Proteomics. Clinical applications》2008,2(7-8):1025-1035
The pathogenesis of progressive renal allograft injury, which is termed chronic allograft nephropathy (CAN), remains obscure and is currently defined by histology. Prospective protocol-biopsy trials have demonstrated that clinical and standard laboratory tests are insufficiently sensitive indicators of the development and progression of CAN. The study aim was to determine if CAN could be characterized by urinary proteomic data and identify the proteins associated with disease. The urinary proteome of 75 renal transplant recipients and 20 healthy volunteers was analyzed using surface enhanced laser desorption and ionization MS. Patients could be classified into subgroups with normal histology and Banff CAN grades 2-3 with a sensitivity of 86% and a specificity of 92% by applying the classification algorithm Adaboost to urinary proteomic data. Several urinary proteins associated with advanced CAN were identified including α1-microglobulin, β2-microglobulin, prealbumin, and endorepellin, the antiangiogenic C-terminal fragment of perlecan. Increased urinary endorepellin was confirmed by ELISA and increased tissue expression of the endorepellin/perlecan ratio by immunofluoresence analysis of renal biopsies. In conclusion, analysis of urinary proteomic data has further characterized the more severe CAN grades and identified urinary endorepellin, as a potential biomarker of advanced CAN. 相似文献
999.
Gene expression changes in a transgenic mouse model overexpressing human wildtype and mutant torsinA
Grundmann K Hübener J Häbig K Reischmann B Poths S Hauser TK Magg J Riess O Bonin M Nguyen HP 《Proteomics. Clinical applications》2008,2(5):720-736
Primary torsion dystonia is an autosomal-dominantly inherited, neurodevelopmental movement disorder caused by a GAG deletion (ΔGAG) in the DYT1 gene, encoding torsinA. This mutation is responsible for approximately 70% of cases of early-onset primary torsion dystonia. The function of wildtype torsinA is still unknown, and it is unsolved how the deletion in the DYT1 gene contributes to the development of the disease. To better understand the molecular processes involved in torsinA pathology, we used genome-wide oligonucleotide microarrays to characterize gene expression patterns in the striatum of mouse models overexpressing the human wildtype and mutant torsinA. By this approach we were able to detect gene expression changes that seem to be specific for torsinA pathology. We found an impact of torsinA, independent from genotype, on vesicle trafficking, exocytosis, and neurotransmitter release in our mouse model. In addition, we were able to identify several new pathways and processes involved in the development of the nervous system that are affected by wildtype and mutant torsinA. Furthermore, we have striking evidence from our gene expression data that glutamate receptor mediated synaptic plasticity in the striatum is the affected underlying cellular process for impaired motor learning in human ΔGAG torsinA transgenic mice. 相似文献
1000.