Ferrichrome, a fungal-type siderophore, confers high ammonium tolerance to fission yeast.

Microorganisms and plants produce siderophores, which function to transport environmental iron into cells as well as participate in cellular iron use and deposition. Their biological functions are diverse although their role in primary metabolism is poorly understood. Ferrichrome is a fungal-type siderophore synthesized by nonribosomal peptide synthetase (NRPS). Herein we show that ferrichrome induces adaptive growth of fission yeast on high ammonium media. Ammonium is a preferred nitrogen source as it suppresses uptake and catabolism of less preferred nitrogen sources such as leucine through a mechanism called nitrogen catabolite repression (NCR). Therefore, the growth of fission yeast mutant cells with leucine auxotrophy is suppressed in the presence of high concentrations of ammonium. This growth suppression was canceled by ferrichrome in a manner dependent on the amino acid transporter Cat1. Additionally, growth retardation of wild-type cells by excess ammonium was exacerbated by deleting the NRPS gene sib1, which is responsible for the biosynthesis of ferrichrome, suggesting that intrinsically produced ferrichrome functions in suppressing the metabolic action of ammonium. Furthermore, ferrichrome facilitated the growth of both wild-type and sib1-deficient cells under low glucose conditions. These results suggest that intracellular iron regulates primary metabolism, including NCR, which is mediated by siderophores.

Serine catabolism produces ROS, sensitizes cells to actin dysfunction, and suppresses cell growth in fission yeast.

Serine is an essential component in organisms as a building block of biomolecules, a precursor of metabolites, an allosteric regulator of an enzyme, etc. This amino acid is thought to be a key metabolite in human diseases including cancers and infectious diseases. To understand the consequence of serine catabolism, we screened natural products to identify a fungal metabolite chaetoglobosin D (ChD) as a specific inhibitor of fission yeast cell growth when cultivated with serine as a sole nitrogen source. ChD targets actin, and actin mutant cells showed severe growth defect on serine medium. ROS accumulated in cells when cultivated in serine medium, while actin mutant cells showed increased sensitivity to oxidative stress. ROS production is a new aspect of serine metabolism, which might be involved in disease progression, and actin could be the drug target for curing serine-dependent symptoms.