Home About us Contact
|
Home About us Contact | ||
|
|
||
Mechanistic Features (mechanistic + feature)
Selected AbstractsMolecular basis of antibiotic resistance and ,-lactamase inhibition by mechanism-based inactivators: perspectives and future directionsFEMS MICROBIOLOGY REVIEWS, Issue 3 2000Christian Therrien Abstract Antibacterial chemotherapy is particularly striking in the family of penicillins and cephalosporins. Over 40 structurally different ,-lactam molecules are available in 73 formulations and the majority of them are currently prescribed for medical use in hospitals. ,-Lactams are well tolerated by humans with few side effects. They interact very specifically with their bacterial target, the d -alanyl- d -alanine carboxypeptidase-transpeptidase usually referred to as dd -peptidase. The outstanding number of ,-lactamases produced by bacteria represent a serious threat to the clinical utility of ,-lactams. The discovery of ,-lactamase inhibitors was thought to solve, in part, the problem of resistance. Unfortunately, bacteria have evolved new mechanisms of resistance to overcome the inhibitory effects of ,-lactamase inactivators. Here, we summarize the diversified mechanistic features of class A ,-lactamases interactions with mechanism-based inhibitors using available microbiological, kinetic and structural data for the prototype TEM ,-lactamases. A brief historical overview of the strategies developed to counteract ,-lactamases will be presented followed by a short description of the chemical events which lead to the inactivation of TEM ,-lactamase by inhibitors from different classes. Finally, an update on the clinical prevalence of natural and inhibitor-resistant enzyme mutants, the total chemical synthesis to design and synthesize a new structure and produced a broad spectrum ,-lactamase inhibitor that mimics the ,-lactam ring, but does not contain it is discussed. [source] Rate coefficients for the gas-phase reaction of hydroxyl radicals with the dimethylbenzaldehydesINTERNATIONAL JOURNAL OF CHEMICAL KINETICS, Issue 9 2006Grainne M. Clifford Rate coefficients for the reactions of hydroxyl (OH) radicals with the dimethylbenzaldehydes have been determined at 295 ± 2K and atmospheric pressure using the relative rate technique. Experiments were performed in an atmospheric simulation chamber using gas chromatography for chemical analysis. The rate coefficients (in units of cm3 molecule,1 s,1) are: 2,3-dimethylbenzaldehyde, (25.9 ± 2.8) × 10,12; 2,4-dimethylbenzaldehyde, (27.5 ± 4.4) × 10,12; 2,5-dimethylbenzaldehyde, (27.6 ± 5.1) × 10,12; 2,6-dimethylbenzaldehyde, (30.7 ± 3.0) × 10,12; 3,4-dimethylbenzaldehyde, (24.6 ± 4.0) × 10,12; and 3,5-dimethylbenzaldehyde, (28.2 ± 2.5) × 10,12. The reactivity of the dimethylbenzaldehydes is compared with other aromatic compounds and it is shown that the magnitude of the OH rate coefficients does not depend significantly on the position of the CH3 substituent on the aromatic ring. The rate coefficient data are explained in terms of known mechanistic features of the reactions and the atmospheric implications are also discussed. © 2006 Wiley Periodicals, Inc. Int J Chem Kinet 38: 563,569, 2006 [source] Structural and functional features of factor XIJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2009D. GAILANI Summary., Factor XI (FXI) has structural and mechanistic features that distinguish it from other coagulation proteases. A relatively recent addition to vertebrate plasma coagulation, FXI is a homodimer, with each subunit containing four apple domains and a protease domain. The apple domains form a disk structure with binding sites for platelets, high molecular weight kininogen, and the substrate factor IX (FIX). FXI is converted to the active protease FXIa by cleavage of the Arg369,Ile370 bond on each subunit. This converts the catalytic domains to the active forms, and unmasks exosites on the apple domains required for FIX binding. FXI activation by factor XIIa or thrombin proceeds through an intermediate with only one activated submit (1/2-FXIa). 1/2-FXIa activates FIX in a similar manner to FXIa. While the importance of the homodimeric structure of FXI is not certain, it may represent a strategy for binding to FIX and a platelet surface simultaneously. [source] Remodeling protein complexes: Insights from the AAA+ unfoldase ClpX and Mu transposasePROTEIN SCIENCE, Issue 8 2005Briana M. Burton Abstract Multiprotein complexes in the cell are dynamic entities that are constantly undergoing changes in subunit composition and conformation to carry out their functions. The protein,DNA complex that promotes recombination of the bacteriophage Mu is a prime example of a complex that must undergo specific changes to carry out its function. The Clp/Hsp100 family of AAA+ ATPases plays a critical role in mediating such changes. The Clp/Hsp100 unfolding enzymes have been extensively studied for the roles they play in protein degradation. However, degradation is not the only fate for proteins that come in contact with the ATP-dependent unfolding enzymes. The Clp/Hsp100 enzymes induce structural changes in their substrates. These structural changes, which we refer to as "remodeling," ultimately change the biological activity of the substrate. These biological changes include activation, inactivation (not associated with degradation), and relocation within the cell. Analysis of the interaction between Escherichia coli ClpX unfoldase and the Mu recombination complex, has provided molecular insight into the mechanisms of protein remodeling. We discuss the key mechanistic features of the remodeling reactions promoted by ClpX and possible implications of these findings for other biological reactions. [source] From cofactor to enzymes.THE CHEMICAL RECORD, Issue 6 2001-phosphate-dependent enzymes, The molecular evolution of pyridoxal- Abstract The pyridoxal-5,-phosphate (vitamin B6)-dependent enzymes that act on amino acid substrates have multiple evolutionary origins. Thus, the common mechanistic features of B6 enzymes are not accidental historical traits but reflect evolutionary or chemical necessities. The B6 enzymes belong to four independent evolutionary lineages of paralogous proteins, of which the , family (with aspartate aminotransferase as the prototype enzyme) is by far the largest and most diverse. The considerably smaller , family (tryptophan synthase , as the prototype enzyme) is structurally and functionally more homogenous. Both the D -alanine aminotransferase family and the alanine racemase family consist of only a few enzymes. The primordial pyridoxal-5,-phosphate-dependent protein catalysts apparently first diverged into reaction-specific protoenzymes, which then diverged further by specializing for substrate specificity. Aminotransferases as well as amino acid decarboxylases are found in two different evolutionary lineages, providing examples of convergent enzyme evolution. The functional specialization of most B6 enzymes seems to have already occurred in the universal ancestor cell before the divergence of eukaryotes, archebacteria, and eubacteria 1500 million years ago. Pyridoxal-5,-phosphate must have emerged very early in biological evolution; conceivably, metal ions and organic cofactors were the first biological catalysts. To simulate particular steps of molecular evolution, both the substrate and reaction specificity of existent B6 enzymes were changed by substitution of active-site residues, and monoclonal pyridoxal-5,-phosphate-dependent catalytic antibodies were produced with selection criteria that might have been operative in the evolution of protein-assisted pyridoxal catalysis. © 2001 John Wiley & Sons, Inc. and The Japan Chemical Journal Forum Chem Rec 1:436,447, 2001 [source] 18O-Labeled lipid hydroperoxides and HPLC coupled to mass spectrometry as valuable tools for studying the generation of singlet oxygen in biological systemBIOFACTORS, Issue 1-4 2004Sayuri Miyamoto Abstract Decomposition of lipid hydroperoxides (LOOH) is known to generate toxic products capable to induce tissue injury. We have recently confirmed that decomposition of LOOH into peroxyl radicals is a potential source of singlet oxygen (1O2) in biological system. Using 18O-labeled linoleic acid hydroperoxide (LA18O18OH) in the presence of Ce4+ or Fe+2, we observed the formation of 18O-labeled 1O2 (18[1O2]) by chemical trapping of 1O2 with 9,10-diphenylanthracene (DPA) and detecting the corresponding 18O-labeled DPA endoperoxide (DPA18O18O) by HPLC coupled to tandem mass spectrometry (HPLC-MS/MS). 18O-Labeled alcohol and ketone were also detected providing further evidence for the generation of 1O2by the Russell mechanism. Similarly the reaction of LA18O18OH with peroxynitrite also generated18[1O2]. In conclusion, these results indicates that the use of 18O-labeled LOOH associated with HPLC-MS/MS can be an useful tool to clarify mechanistic features involved in the reaction of LOOH in biological media. [source] Cell entry by human pathogenic arenavirusesCELLULAR MICROBIOLOGY, Issue 4 2008Jillian M. Rojek Summary The arenaviruses Lassa virus (LASV) in Africa and Machupo (MACV), Guanarito (GTOV) and Junin viruses (JUNV) in South America cause severe haemorrhagic fevers in humans with fatality rates of 15,35%. The present review focuses on the first steps of infection with human pathogenic arenaviruses, the interaction with their cellular receptor molecules and subsequent entry into the host cell. While similarities exist in genomic organization, structure and clinical disease caused by pathogenic Old World and New World arenaviruses these pathogens use different primary receptors. The Old World arenaviruses employ ,-dystroglycan, a cellular receptor for proteins of the extracellular matrix, and the human pathogenic New World arenaviruses use the cellular cargo receptor transferrin receptor 1. While the New World arenavirus JUNV enters cells via clathrin-dependent endocytosis, evidence occurred for clathrin-independent entry of the prototypic Old World arenavirus lymphocytic choriomeningitis virus. Upon internalization, arenaviruses are delivered to the endosome, where pH-dependent membrane fusion is mediated by the envelope glycoprotein (GP). While arenavirus GPs share characteristics with class I fusion GPs of other enveloped viruses, unusual mechanistic features of GP-mediated membrane fusion have recently been discovered for arenaviruses with important implications for viral entry. [source] | |||||||||||||