A yeast model of 5-oxoproline accumulation reveals a general toleration to 5-oxoproline

5-oxoproline (5-OP) or pyroglutamic acid is an intermediate of the degradation arc of the glutathione cycle. It is metabolized into glutamate through the action of the 5-oxoprolinase enzyme, the only enzyme known to act on this metabolite. 5-OP has long been known to be relatively inert with a proposed role as an osomoprotectant. Recent studies on the 5-oxoprolinase enzyme in mammalian cells have, however, shown that knockdown or deletions of the 5-oxoprolinase make mice (and humans) prone to heart failure. This was ascribed to oxidative stress due to a two-fold elevation in 5-OP. To examine the consequences of 5-oxoproline accumulation more rigorously, we have created a yeast model for 5-oxoproline accumulation. We observed retardation of growth only when intracellular levels of 5-OP were increased 12-20 fold over the normal levels. A transcriptomics study was carried out under these conditions. We observed that while a large number of genes were regulated upto 2-fold, there were no single prominent pathways amongst them. Among the key genes upregulated were different efflux pumps. Using knockouts and also overexpression of selected genes, we could observe that many of the upregulated genes were involved in the cellular response to 5-OP accumulation. However, it did not appear that there was any significant oxidative stress response. The study suggests a need to reevaluate previous suppositions of the 5-OP induced oxidative stress response. Instead, we propose an alternative model to explain the possible consequences of 5-oxoprolinase deficiency based on these findings made with the yeast model.