MFS transporters required for multidrug/multixenobiotic (MD/MX) resistance in the model yeast: understanding their physiological function through post-genomic approaches

Abstract

Multidrug/Multixenobiotic resistance (MDR/MXR) is a widespread phenomenon with clinical, agricultural and biotechnological implications, where MDR/MXR transporters that are presumably able to catalyze the efflux of multiple cytotoxic compounds play a key role in the acquisition of resistance. However, although these proteins have been traditionally considered drug exporters, the physiological function of MDR/MXR transporters and the exact mechanism of their involvement in resistance to cytotoxic compounds are still open to debate. In fact, the wide range of structurally and functionally unrelated substrates that these transporters are presumably able to export has puzzled researchers for years. The discussion has now shifted toward the possibility of at least some MDR/MXR transporters exerting their effect as the result of a natural physiological role in the cell, rather than through the direct export of cytotoxic compounds, while the hypothesis that MDR/MXR transporters may have evolved in nature for other purposes than conferring chemoprotection has been gaining momentum in recent years. This review focuses on the drug transporters of the Major Facilitator Superfamily (MFS; drug:H(+) antiporters) in the model yeast Saccharomyces cerevisiae. New insights into the natural roles of these transporters are described and discussed, focusing on the knowledge obtained or suggested by post-genomic research. The new information reviewed here provides clues into the unexpectedly complex roles of these transporters, including a proposed indirect regulation of the stress response machinery and control of membrane potential and/or internal pH, with a special emphasis on a genome-wide view of the regulation and evolution of MDR/MXR-MFS transporters.

Keywords: MDR/MXR transporters; Major Facilitator Superfamily (MFS); Saccharomyces cerevisiae; genome-wide approaches; multidrug/multixenobiotic resistance (MDR/MXR); phylogenetic analysis; transcriptional regulation.

Figure 1

Phylogenetic tree constructed using the amino acid sequences of DHA1 and DAG proteins encoded in the genome of the model-organism S. cerevisiae. The multiple alignments of the protein sequences were done using Muscle software and the tree was built using the maximum likelihood package (PROTML) made available in the PHYLIP software suite (Felsenstein, ; Edgar, 2004).

Figure 2

Transcriptional regulatory networks that control the expression of DHA/DAG genes, considering the subgroups of transcription factors known to be involved in multidrug resistance (A), in stress response (B), lipid metabolism (C), or in the response to amino acid (D) and carbon source (E) availability. The displayed regulatory associations are according to the data present in the Yeastract database (www.yeastract.com, Teixeira et al., 2006, 2014), as of February 2014. Arrows indicate the experimental basis of the documented regulatory associations, either expression evidence (blue arrows) or DNA-binding evidence (red arrows). Bold arrows indicate the cases in which the regulatory association was found to take place in response to the environmental condition considered in each subgroup of transcription factors.