The Pdr12 ABC transporter for the development of weak organic acid resistance in yeast

Department of Molecular Genetics, University and Biocenter of Vienna, Austria.
The EMBO Journal (Impact Factor: 10.43). 09/1998; 17(15):4257-65. DOI: 10.1093/emboj/17.15.4257
Source: PubMed


Exposure of Saccharomyces cerevisiae to sorbic acid strongly induces two plasma membrane proteins, one of which is identified in this study as the ATP-binding cassette (ABC) transporter Pdr12. In the absence of weak acid stress, yeast cells grown at pH 7.0 express extremely low Pdr12 levels. However, sorbate treatment causes a dramatic induction of Pdr12 in the plasma membrane. Pdr12 is essential for the adaptation of yeast to growth under weak acid stress, since Deltapdr12 mutants are hypersensitive at low pH to the food preservatives sorbic, benzoic and propionic acids, as well as high acetate levels. Moreover, active benzoate efflux is severely impaired in Deltapdr12 cells. Hence, Pdr12 confers weak acid resistance by mediating energy-dependent extrusion of water-soluble carboxylate anions. The normal physiological function of Pdr12 is perhaps to protect against the potential toxicity of weak organic acids secreted by competitor organisms, acids that will accumulate to inhibitory levels in cells at low pH. This is the first demonstration that regulated expression of a eukaryotic ABC transporter mediates weak organic acid resistance development, the cause of widespread food spoilage by yeasts. The data also have important biotechnological implications, as they suggest that the inhibition of this transporter could be a strategy for preventing food spoilage.

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    • "We have focused on the physiological function of a member of the pleiotropic drug resistance (PDR) subfamily of ABC transporters, members of which have been identified in yeast and plants, but not so far in animals. PDR-like ABC transporters were first described in yeast, where they confer resistance to a multitude of toxins and organic acids (Decottignies and Goffeau 1997, Piper et al. 1998). Many natural products synthesized in plant cells are candidate substrates for ABC transporters, and are transported across the membranes of plant tissues. "

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    • "PDR12 was the only known WAR1-dependent gene with an eQTL mapping at WAR1 (even with a LODscore below the threshold) [45]. As PDR12 has been implicated in sorbic acid resistance [46], we investigated whether variation of the expression of this gene modulated resistance to this acid. We assessed the growth of segregants in the synthetic medium (pH3.3) "
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    ABSTRACT: Variation of gene expression can lead to phenotypic variation and have therefore been assumed to contribute the diversity of wine yeast (Saccharomyces cerevisiae) properties. However, the molecular bases of this variation of gene expression are unknown. We addressed these questions by carrying out an integrated genetical-genomic study in fermentation conditions. We report here quantitative trait loci (QTL) mapping based on expression profiling in a segregating population generated by a cross between a derivative of the popular wine strain EC1118 and the laboratory strain S288c. Most of the fermentation traits studied appeared to be under multi-allelic control. We mapped five phenotypic QTLs and 1465 expression QTLs. Several expression QTLs overlapped in hotspots. Among the linkages unraveled here, several were associated with metabolic processes essential for wine fermentation such as glucose sensing or nitrogen and vitamin metabolism. Variations affecting the regulation of drug detoxification and export (TPO1, PDR12 or QDR2) were linked to variation in four genes encoding transcription factors (PDR8, WAR1, YRR1 and HAP1). We demonstrated that the allelic variation of WAR1 and TPO1 affected sorbic and octanoic acid resistance, respectively. Moreover, analysis of the transcription factors phylogeny suggests they evolved with a specific adaptation of the strains to wine fermentation conditions. Unexpectedly, we found that the variation of fermentation rates was associated with a partial disomy of chromosome 16. This disomy resulted from the well known 8--16 translocation. This large data set made it possible to decipher the effects of genetic variation on gene expression during fermentation and certain wine fermentation properties Our findings shed a new light on the adaptation mechanisms required by yeast to cope with the multiple stresses generated by wine fermentation. In this context, the detoxification and export systems appear to be of particular importance, probably due to nitrogen starvation. Furthermore, we show that the well characterized 8--16 translocation located in SSU1, which is associated with sulfite resistance, can lead to a partial chromosomic amplification in the progeny of strains that carry it, greatly improving fermentation kinetics. This amplification has been detected among other wine yeasts.
    BMC Genomics 10/2013; 14(1):681. DOI:10.1186/1471-2164-14-681 · 3.99 Impact Factor
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    • "There has been more success in identification of carboxylic acid transporters in S. cerevisiae than in E. coli. The Pdr12 ABC transporter was originally discovered during a study of sorbic (2,4- hexadienoic) acid toxicity and was shown to contribute to organic acid tolerance through the energy-dependent removal of carboxylate anions from the cell interior (Piper et al., 1998). Presumably Pdr12 is the transporter proposed to be necessary for acquisition of octanoic acid tolerance in other studies (Cabral et al., 2001), as it has since been shown to contribute to octanoic acid tolerance in S. cerevisiae, along with the Tpo1p transporter (Legras et al., 2010). "
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    ABSTRACT: Carboxylic acids are an attractive biorenewable chemical in terms of their flexibility and usage as precursors for a variety of industrial chemicals. It has been demonstrated that such carboxylic acids can be fermentatively produced using engineered microbes, such as Escherichia coli and Saccharomyces cerevisiae. However, like many other attractive biorenewable fuels and chemicals, carboxylic acids become inhibitory to these microbes at concentrations below the desired yield and titer. In fact, their potency as microbial inhibitors is highlighted by the fact that many of these carboxylic acids are routinely used as food preservatives. This review highlights the current knowledge regarding the impact that saturated, straight-chain carboxylic acids, such as hexanoic, octanoic, decanoic, and lauric acids can have on E. coli and S. cerevisiae, with the goal of identifying metabolic engineering strategies to increase robustness. Key effects of these carboxylic acids include damage to the cell membrane and a decrease of the microbial internal pH. Certain changes in cell membrane properties, such as composition, fluidity, integrity, and hydrophobicity, and intracellular pH are often associated with increased tolerance. The availability of appropriate exporters, such as Pdr12, can also increase tolerance. The effect on metabolic processes, such as maintaining appropriate respiratory function, regulation of Lrp activity and inhibition of production of key metabolites such as methionine, are also considered. Understanding the mechanisms of biocatalyst inhibition by these desirable products can aid in the engineering of robust strains with improved industrial performance.
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