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

ABSTRACT: 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.

SUBMITTER: Chiu PC

PROVIDER: S-EPMC9613971 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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

Chiu Po-Chang PC Nakamura Yuri Y Nishimura Shinichi S Tabuchi Toshitsugu T Yashiroda Yoko Y Hirai Go G Matsuyama Akihisa A Yoshida Minoru M

Scientific reports 20221027 1

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 sourc ...[more]

PMID: 36302945

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Project description:BackgroundSiderophores are small iron-binding molecules produced by microorganisms to facilitate iron acquisition from the environment. Radiolabelled siderophores offer a promising solution for infection imaging, as they can specifically target the pathophysiological mechanisms of pathogens. Gallium-68 can replace the iron in siderophores, enabling molecular imaging with positron emission tomography (PET). Stereospecific interactions play a crucial role in the recognition of receptors, transporters, and iron utilisation. Furthermore, these interactions have an impact on the host environment, affecting pharmacokinetics and biodistribution. This study examines the influence of siderophore stereoisomerism on imaging properties, with a focus on ferrirubin (FR) and ferrirhodin (FRH), two cis-trans isomeric siderophores of the ferrichrome type.ResultsTested siderophores were labelled with gallium-68 with high radiochemical purity. The resulting complexes differed in their in vitro characteristics. [68Ga]Ga-FRH showed less hydrophilic properties and higher protein binding values than [68Ga]Ga-FR. The stability studies confirmed the high radiochemical stability of both [68Ga]Ga-siderophores in all examined media. Both siderophores were found to be taken up by S. aureus, K. pneumoniae and P. aeruginosa with similar efficacy. The biodistribution tested in normal mice showed rapid renal clearance with low blood pool retention and fast clearance from examined organs for [68Ga]Ga-FR, whereas [68Ga]Ga-FRH showed moderate retention in blood, resulting in slower pharmacokinetics. PET/CT imaging of mice injected with [68Ga]Ga-FR and [68Ga]Ga-FRH confirmed findings from ex vivo biodistribution studies. In a mouse model of S. aureus myositis, both radiolabeled siderophores showed radiotracer accumulation at the site of infection.ConclusionsThe 68Ga-complexes of stereoisomers ferrirubin and ferrirhodin revealed different pharmacokinetic profiles. In vitro uptake was not affected by isomerism. Both compounds had uptake with the same bacterial culture with similar efficacy. PET/CT imaging showed that the [68Ga]Ga-complexes accumulate at the site of S. aureus infection, highlighting the potential of [68Ga]Ga-FR as a promising tool for infection imaging. In contrast, retention of the radioactivity in the blood was observed for [68Ga]Ga-FRH. In conclusion, the stereoisomerism of potential radiotracers should be considered, as even minor structural differences can influence their pharmacokinetics and, consequently, the results of PET imaging.

Dataset Information

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

Publications

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

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