γ-Glu dipeptides are ubiquitous in nature, and yet their metabolism and transport are poorly understood. Here we investigate this using the dipeptide γ-Glu-met in Saccharomyces cerevisiae. γ-Glu-met was efficiently utilized by S. cerevisiae, and using a transcriptomics approach, followed by a genetic screen, we identified Seo1p, an orphan transporter of yeast, as the transporter of γ-Glu-met. Uptake studies confirmed Seo1p as a high affinity (Km =48μM), highly specific transporter of γ-Glu-met since other analogs like n-Glu-met, γ-Glu-leu, γ-Glu-cys, γ-Glu-met-gly, methionine and methionine sulfoxide were not transported by Seo1p. The expression of SEO1 was also repressed by these sulfur sources in the medium, but it was derepressed in the presence of γ-Glu-met. Seo1p homologs were present in yeast and fungi, and both Candida auris and Candida albicans were found to encode a functional Seo1p. The intracellular degradation of γ-Glu-met was investigated and found to be dependent on both the glutathione degrading cytosolic Dug2p/Dug3p complex, and the vacuolar γ-glutamyl transpeptidase, Ecm38p. Opt2p, a member of the oligopeptide transporter family, was also identified in the screen, and deletions in OPT2 led to an inability to grow on γ-Glu-met. However, Opt2p was not primarily involved in γ-Glu-met uptake. Its deletion affected vacuolar biogenesis, that interfered with the degradation of the peptide through Ecm38p. These studies demonstrate how organisms have evolved dedicated pathways for the uptake of these unusual peptides.

• PMID: 40288644
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Journal Article

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Dubey P, Ahmad MS, Laxman S, Bachhawat AK

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