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Parallel Routes (parallel + route)
Selected AbstractsA Fast and Parallel Route to Cyclic Isothioureas and Guanidines with Use of Microwave-Assisted Chemistry.CHEMINFORM, Issue 29 2004Helena Sandin Abstract For Abstract see ChemInform Abstract in Full Text. [source] A Fast and Parallel Route to Cyclic Isothioureas and Guanidines with Use of Microwave-Assisted Chemistry.CHEMINFORM, Issue 29 2004Helena Sandin Abstract For Abstract see ChemInform Abstract in Full Text. [source] Molecular evidence-based medicineEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 5 2007Evolution, integration of information in the genomic era Abstract Evidence-based medicine and molecular medicine have both been influential in biomedical research in the last 15 years. Despite following largely parallel routes to date, the goals and principles of evidence-based and molecular medicine are complementary and they should be converging. I define molecular evidence-based medicine as the study of medical information that makes sense of the advances of molecular biological disciplines and where errors and biases are properly appreciated and placed in context. Biomedical measurement capacity improves very rapidly. The exponentially growing mass of hypotheses being tested requires a new approach to both statistical and biological inference. Multidimensional biology requires careful exact replication of research findings, but indirect corroboration is often all that is achieved at best. Besides random error, bias remains a major threat. It is often difficult to separate bias from the spirit of scientific inquiry to force data into coherent and ,significant' biological stories. Transparency and public availability of protocols, data, analyses and results may be crucial to make sense of the complex biology of human disease and avoid being flooded by spurious research findings. Research efforts should be integrated across teams in an open, sharing environment. Most research in the future may be designed, performed, and integrated in the public cyberspace. [source] Experimental validation of metabolic pathway modelingFEBS JOURNAL, Issue 13 2008An illustration with glycolytic segments from Entamoeba histolytica In the search for new drug targets in the human parasite Entamoeba histolytica, metabolic control analysis was applied to determine, experimentally, flux control distribution of amebal glycolysis. The first (hexokinase, hexose-6-phosphate isomerase, pyrophosphate-dependent phosphofructokinase (PPi -PFK), aldolase and triose-phosphate isomerase) and final (3-phosphoglycerate mutase, enolase and pyruvate phosphate dikinase) glycolytic segments were reconstituted in vitro with recombinant enzymes under near-physiological conditions of pH, temperature and enzyme proportion. Flux control was determined by titrating flux with each enzyme component. In parallel, both glycolytic segments were also modeled by using the rate equations and kinetic parameters previously determined. Because the flux control distribution predicted by modeling and that determined by reconstitution were not similar, kinetic interactions among all the reconstituted components were experimentally revised to unravel the causes of the discrepancy. For the final segment, it was found that 3-phosphoglycerate was a weakly competitive inhibitor of enolase, whereas PPi was a moderate inhibitor of 3-phosphoglycerate mutase and enolase. For the first segment, PPi was both a strong inhibitor of aldolase and a nonessential mixed-type activator of amebal hexokinase; in addition, lower Vmax values for hexose-6-phosphate isomerase, PPi -PFK and aldolase were induced by PPi or ATP inhibition. It should be noted that PPi and other metabolites were absent from the 3-phosphoglycerate mutase and enolase or aldolase and hexokinase kinetics experiments, but present in reconstitution experiments. Only by incorporating these modifications in the rate equations, modeling predicted values of flux control distribution, flux rate and metabolite concentrations similar to those experimentally determined. The experimentally validated segment models allowed ,in silico experimentation' to be carried out, which is not easy to achieve in in vivo or in vitro systems. The results predicted a nonsignificant effect on flux rate and flux control distribution by adding parallel routes (pyruvate kinase for the final segment and ATP-dependent PFK for the first segment), because of the much lower activity of these enzymes in the ameba. Furthermore, modeling predicted full flux-control by 3-phosphoglycerate mutase and hexokinase, in the presence of low physiological substrate and product concentrations. It is concluded that the combination of in vitro pathway reconstitution with modeling and enzyme kinetics experimentation permits a more comprehensive understanding of the pathway behavior and control properties. [source] Hydrolytic Reactions of Thymidine 5,- O -Phenyl- N -Alkylphosphoramidates, Models of Nucleoside 5,-Monophosphate ProdrugsCHEMISTRY - A EUROPEAN JOURNAL, Issue 30 2007Mikko Ora Dr. Abstract To obtain detailed data on the kinetics of hydrolytic reactions of triester-like nucleoside 5,- O -aryl- N -alkylphosphoramidates, potential prodrugs of antiviral nucleoside monophosphates, the hydrolysis of diastereomeric (RP/SP) thymidine 5,-{O -phenyl- N -[(1S)-2-oxo-2-methoxy-1-methylethyl]phosphoramidate} (3), a phosphoramidate derived from the methyl ester of L -alanine, has been followed by reversed-phase HPLC over the range from H0=0 to pH,8 at 90,°C. According to the time-dependent product distributions, the hydrolysis of 3 proceeds at pH<4 by two parallel routes, namely by nucleophilic displacement of the alaninyl ester moiety by a water molecule and by hydrolysis of the carboxylic ester linkage that allows intramolecular attack of the carboxy group on the phosphorus atom, thereby resulting in the departure of either thymidine or phenol without marked accumulation of any intermediates. Both routes represent about half of the overall disappearance of 3. The departure of phenol eventually leads to the formation of thymidine 5,-phosphate. At pH>5, the predominant reaction is hydrolysis of the carboxylic ester linkage followed by intramolecular displacement of a phenoxide ion by the carboxylate ion and hydrolysis of the resulting cyclic mixed anhydride into an acyclic diester-like thymidine 5,-phosphoramidate. The latter product accumulated quantitatively without any indication of further decomposition. Hydroxide-ion-catalyzed POPh bond cleavage of the starting material 3 occurred as a side reaction. Comparative measurements with thymidine 5,-{N -[(1S)-2-oxo-2-methoxy-1-methylethyl]phosphoramidate} (4) revealed that, under acidic conditions, this diester-like compound is hydrolyzed by PN bond cleavage three orders of magnitude more rapidly than the triester-like 3. At pH>5, the stability order is reversed, with 3 being hydrolyzed six times as rapidly as 4. Mechanisms of the partial reactions are discussed. [source] | ||||||||||