PMID:15371426

Citation	Rotem, D and Schuldiner, S (2004) EmrE, a multidrug transporter from Escherichia coli, transports monovalent and divalent substrates with the same stoichiometry. J. Biol. Chem. 279:48787-93
Abstract	Multidrug transporters recognize and transport substrates with apparently little common structural features. At times these substrates are neutral, negatively, or positively charged, and only limited information is available as to how these proteins deal with the energetic consequences of transport of substrates with different charges. Multidrug transporters and drug-specific efflux systems are responsible for clinically significant resistance to chemotherapeutic agents in pathogenic bacteria, fungi, parasites, and human cancer cells. Understanding how these efflux systems handle different substrates may also have practical implications in the development of strategies to overcome the resistance mechanisms mediated by these proteins. Here, we compare transport of monovalent and divalent substrates by EmrE, a multidrug transporter from Escherichia coli, in intact cells and in proteoliposomes reconstituted with the purified protein. The results demonstrated that whereas the transport of monovalent substrates involves charge movement (i.e. electrogenic), the transport of divalent substrate does not (i.e. electroneutral). Together with previous results, these findings suggest that an EmrE dimer exchanges two protons per substrate molecule during each transport cycle. In intact cells, under conditions where the only driving force is the electrical potential, EmrE confers resistance to monovalent substrates but not to divalent ones. In the presence of proton gradients, resistance to both types of substrates is detected. The finding that under some conditions EmrE does not remove certain types of drugs points out the importance of an in-depth understanding of mechanisms of action of multidrug transporters to devise strategies for coping with the problem of multidrug resistance.
Links	PubMed Online version:10.1074/jbc.M408187200
Keywords	Acriflavine/pharmacology; Antiporters/chemistry; Antiporters/physiology; Biological Transport; Carbonyl Cyanide m-Chlorophenyl Hydrazone/pharmacology; Dimerization; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Escherichia coli/metabolism; Escherichia coli Proteins; Ethidium/pharmacology; Hydrogen-Ion Concentration; Indicators and Reagents/pharmacology; Inhibitory Concentration 50; Ionophores/pharmacology; Liposomes/chemistry; Membrane Potentials; Membrane Proteins/chemistry; Membrane Proteins/physiology; Onium Compounds/pharmacology; Organophosphorus Compounds/pharmacology; Paraquat/pharmacology; Plasmids/metabolism; Proteolipids/chemistry; Protons; Time Factors; Uncoupling Agents/pharmacology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
ECOLI:EMRE	enables	GO:0015307: obsolete drug:proton antiporter activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete

References

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