Plasma membrane folate transport in fungi and plants is mediated by members of the oligopeptide transporter (OPT) family

Abstract

Folates are essential for all organisms. They are acquired either through de novo biosynthesis or from the diet. Yeast, fungi, and plants make their own folates, and it has not been clear if plasma membrane folate transporters exist in these organisms. Using a synthetic lethal screen in Saccharomyces cerevisiae, we observed that deletions in a gene encoding the previously identified glutathione (GSH) transporter, OPT1, exhibited severe growth defects with a disruption in folate biosynthesis. Uptake experiments confirmed that Opt1p/Hgt1p can transport folinic acid and the naturally abundant methyl tetrahydrofolate. As S. cerevisiae Opt1p was able to transport both folate and GSH, we used alanine-scanning mutants in the transmembrane domains of the channel pore to identify the residues required specifically for the uptake of folates and distinct from those required for GSH. We further examined the oligopeptide transporter (OPT) family of other organisms for the presence of folate transporters. In C. albicans, CaOPT1, the ortholog of S. cerevisiae OPT1, efficiently transported folate but not GSH, while the previously characterized GSH transporter, CaOPT7, could not transport folate. Aspergillus fumigatus has eight homologs of the OPT family, of which OptB and OptH transport folates. In the plant Arabidopsis thaliana, the Opt1 homologs AtOpt2, AtOpt4, and AtOpt6 transport folates. This discovery of folate transporters across fungi and plants fills a critical gap in our understanding of folate metabolism and can benefit the exploitation of these pathways in pathogenic fungi and in plants.