This chapter contains sections titled: Introduction Structural Overview Role in Cell Survival The Role of TGase-2 in Cancer Cell Migration and Invasion Role in Anchorage-Independent Growth Concluding Remarks/Questions for the Future References
This chapter contains sections titled: Overview Paracatalytic Reactions: Definition Discovery of Enzyme-Catalyzed Oxygenase Side Reactions: Rubisco Reaction of Carbanions with Oxygen Catalyzed by Selected Enzymes (Excluding Pyridoxal 50′-Phosphate-Containing Enzymes) Oxidation Reactions Catalyzed by PLP-Containing Amino Acid Decarboxylases Mechanisms Contributing to the Oxidation Reactions Catalyzed by PLP-Containing Amino Acid Decarboxylases Paracatalytic Oxidation of the α-Ketoglutarate Dehydrogenase-Generated Carbanion Potential Role of Paracatalytic Side Reactions in Diseases Conclusions Acknowledgements References
This chapter contains sections titled: Transglutaminases Cell Death Autophagy TG2 In Diseases Conclusions Acknowledgments References
This chapter contains sections titled: Introduction Hb Koln Disease, A Prototype of Erythrocyte Disorders Characterized by the Presence of γ:ε-Bonded, Abnormal Membrane Skeletal Polymers The Ca2+-Enriched Human Red Blood Cell as Model for the Physical and Biochemical Abnormalities Observed in Erythrocyte Diseases with Shortened Cell Lifespan The Polydisperse Nature of High-Molecular-Weight, γ:ε-Bonded Membrane Skeletal Polymers Generated in Human Erythrocytes With Ca2+ Overload Deciphering the Polypeptide Compositions of the SDS–DTT-Soluble Cores of Cross-Linked Erythrocyte Structures: Immunologic and Proteomic Analysis Inferences from the Analysis of Polypeptide Components of γ:ε-Bonded Cores of Membrane Polymers Found in Human Erythrocytes with Ca2+ Overload Conclusion Acknowledgments References
“…not enough to kill the streptococci but enough to educate them to resist penicillin” (Alexander Fleming, Nobel Prize lecture, Dec. 11, 1945). These prophetic words underscore the arms race in which we find ourselves today. Large populations and mutable genomes give microbes a profound capacity to respond to changing environmental conditions. The misuse of antibiotics in human health and agriculture has contributed to continuing microbial drug resistance. Thus, 65 years later, in 2010, we continue to battle microorganisms and strive to design novel and useful antimicrobial agents (1).
This chapter contains sections titled: Introduction Irreversible Inhibitors Applications of Irreversible TG2 Inhibitors Concluding Remarks References
This chapter contains sections titled: Background Efflux Pumps in Enterobacteriaceae Efflux Pumps in Nonfermentative Gram-Negative Bacilli Efflux Pumps in Gram-Positive Bacteria Efflux Pumps in Other Bacterial Species with Clinical Relevance Plasmid-Encoded Quinolone Efflux Pumps Concluding Remarks Acknowledgements References
This chapter contains sections titled: Introduction Biochemistry of TG2 Molecular Biology of TG2 Physiopathology of TG2 Medical Perspectives and Future Directions Acknowledgments References
This chapter contains sections titled: Introduction Transglutaminase 2 and Celiac Disease Transglutaminase 2 and SLE Like Syndromes Concluding Remarks Acknowledgments References
This chapter contains sections titled: Introduction Revisiting Diseases in Relation to the TGase 2-NF-κB Mechanism Conclusion Acknowledgements References
This chapter contains sections titled: Introduction Structure and Regulation Physiologic Functions of TG2 Disruption of TG2 Functions in Pathologic Conditions Perspectives for Pharmacologic Interventions Concluding Comments Acknowledgements References
This chapter contains sections titled: Introduction Cloning a Putative Efflux Protein into a Plasmid Expression Vector Cultivation of Host Cells Containing the Plasmid Encoding the Target Protein Detection of Histidine-Tagged Efflux Proteins in E. coli Membrane Preparations Solubilization of the Efflux Proteins with Detergents Purification of Histidine-Tagged Efflux Proteins Confirmation of Integrity and Monodispersity of the Purified Protein Crystallization Trials on Purified Proteins Conclusions and Discussion Acknowledgements References
This chapter contains sections titled: Introduction Escherichia coli AcrAB-TolC Efflux System Escherichia coli CusABC Efflux System Campylobacter jejuni CmeABC Efflux System Efflux Pumps of Neisseria gonorrhoeae: Repertoire and Contributions to Antimicrobial Resistance Resistance Concluding Remarks Acknowledgements References
RND (Resistance-Nodulation-Division) family transporters are widespread especially among Gram-negative bacteria, and catalyze the active efflux of many antibiotics and chemotherapeutic agents. They have very large periplasmic domains, and form tripartite complexes with outer membrane channels and periplasmic adaptor proteins. AcrAB–TolC complex of Escherichia coli, which pumps out a very wide range of drugs, has been studied most intensively. Early studies showed that the transporter captures even those substrates that cannot permeate across the cytoplasmic membrane, such as dianionic β-lactams, suggesting that the capture can occur from the periplasm. It was also suggested that the capture occurs from the cytoplasmic membrane/periplasm interface, because most substrates contain a sizable hydrophobic domain; however, this may simply be a reflection of the nature of the binding site within AcrB. Genetic studies of chimeric transporters showed that much of the substrate specificity is determined by their periplasmic domains. Biochemical studies with intact cells recently led to the determination of the kinetic constants of AcrB for some β-lactams, and the result confirms the old prediction that AcrB is a rather slow pump. Reconstitution of purified AcrB and its relatives showed that the pump is a drug/proton antiporter, that AcrA strongly stimulates the activity of the pump, and that AcrB seems to have a highest affinity for conjugated bile salts. Structural study with mutants of the network of charged residues in the transmembrane domain showed that protonation here produced a far-reaching conformational change, which was found to be present in one of the protomers in the asymmetric crystal structure of the wild-type AcrB. The functional rotatory hypothesis then predicts that the drug bound in the periplasmic domain is extruded through this conformational change initiated by the protonation of one of the residues in the aforementioned network, an idea that was recently supported by disulfide cross-linking as well as by the behavior of linked AcrB protomers.
