The multidrug resistance transporters of the major facilitator superfamily, 6 years after disclosure of Saccharomyces cerevisiae genome sequence.
The emergence of multidrug resistance (MDR) plays a crucial role in the failure of treatments of tumors and infectious diseases and in the control of plant pathogens, weeds and food-poisoning and food-spoilage microorganisms. Among the mechanisms underlying the MDR phenomenon in various organisms is the action of transmembrane transport proteins that presumably catalyse the active expulsion of structurally and functionally unrelated cytotoxic compounds out of the cell or their intracellular partitioning. On the basis of the complete genome sequence of Saccharomyces cerevisiae, numerous established and putative multidrug transporters were identified in this non-pathogenic, easy to manipulate eukaryotic model system. In yeast, the putative drug:H(+)-antiporters belong to the major facilitator superfamily; they comprise at least 23 proteins that have largely escaped characterisation by classical approaches. Other MDR determinants are membrane transporters belonging to the ATP binding cassette (ABC) superfamily, that utilize the energy of ATP hydrolysis for activity, and factors for transcriptional regulation of all the MDR transporters. This work reviews the current status of knowledge on the poorly characterized H(+)-antiporters, with 12 and 14 predicted spans, DHA12 and DHA14, drug efflux families. Consideration is given to the inventory and phylogenetic characterization, role as MDR determinants, regulation of gene expression, subcellular localisation and activity as solute transporters. Most of the present knowledge on these putative drug:H(+)-antiporters was driven by disclosure of S. cerevisiae genome sequence, in April 1996, being a paradigm of post-genomic research.
Centro de Engenharia Biológica e Química, Instituto Superior Técnico, Av. Rovisco Pais, 1049-001 Lisboa, Portugal. isacorrei@ist.utl.pt
Isabel
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Sá-Correia
Sandra
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Tenreiro
D026141:Drug Resistance, Multiple, Fungal / Q000235:genetics* / Q000502:physiology; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D016681:Genome, Fungal; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008956:Models, Chemical; D008957:Models, Genetic; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D016366:Open Reading Frames / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D020539:Sequence Analysis, Protein; D017385:Sequence Homology
D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins