Rhodotorula mucilaginosa Growth on Glutamine Is Sensitive to Mammalian-Glutaminase Inhibitors

The extremophile yeast Rhodotorula mucilaginosa can grow in extremely poor environments. Glutamine (Gln) is an important anaplerotic substrate for gluconeogenesis and pentose synthesis. Glutaminase (Glnase) produces glutamate which in turn undergoes transamination to produce the Krebs cycle intermediate α-keto-glutarate. The yeast enzyme has low similarity with human GLS1, although the active site is partially conserved. Also, antibodies against GLS1 cross react with the yeast enzyme. Glnase is a therapeutic mark in tumor treatments, where endogenous Glnase is inhibited with different pharmaceutical agents. Another proposed approach is to add exogenous fungal Glnase to deplete Gln pools, thus starving the tumor. Using Gln as the sole carbon source, R. mucilaginosa grew better than Debaryomyces hansenii, while Saccharomyces cerevisiae did not grow. In addition, the Gln-dependent growth of R. mucilaginosa was inhibited by two different Gln metabolism inhibitors used in cancer therapy, namely 6-diazo-5-oxo-L-norleucine (DON) and Telaglenastat (CB-839). In cell homogenates from R. mucilaginosa DON inhibited Gln metabolism at similar concentrations as those used in mammals. The ability of R. mucilaginosa to grow on Gln as the sole carbon source is exceptional and it may be used as a suitable tool to evaluate agents targeting tumoral Gln metabolism. It is proposed that R. mucilaginosa may be a valuable source of exogenous Glnase.