[en] Maintaining cellular iron homeostasis is critical for organismal survival. Whereas iron depletion negatively affects the many metabolic pathways that depend on the activity of iron-containing enzymes, any excess of iron can cause the rapid formation of highly toxic reactive oxygen species (ROS) through Fenton chemistry. Although several cellular iron chelators have been identified, little is known about if and how organisms can prevent the Fenton reaction. By studying the effects of cisplatin, a commonly used anticancer drug and effective antimicrobial, we discovered that cisplatin elicits severe iron stress and oxidative DNA damage in bacteria. We found that both of these effects are successfully prevented by polyphosphate (polyP), an abundant polymer consisting solely of covalently linked inorganic phosphates. Subsequent in vitro and in vivo studies revealed that polyP provides a crucial iron reservoir under nonstress conditions and effectively complexes free iron and blocks ROS formation during iron stress. These results demonstrate that polyP, a universally conserved biomolecule, plays a hitherto unrecognized role as an iron chelator and an inhibitor of the Fenton reaction.IMPORTANCE How do organisms deal with free iron? On the one hand, iron is an essential metal that plays crucial structural and functional roles in many organisms. On the other hand, free iron is extremely toxic, particularly under aerobic conditions, where iron rapidly undergoes the Fenton reaction and produces highly reactive hydroxyl radicals. Our study now demonstrates that we have discovered one of the first physiologically relevant nonproteinaceous iron chelators and Fenton inhibitors. We found that polyphosphate, a highly conserved and ubiquitous inorganic polyanion, chelates iron and, through its multivalency, prevents the interaction of iron with peroxide and therefore the formation of hydroxyl radicals. We show that polyP provides a crucial iron reservoir for metalloproteins under nonstress conditions and effectively chelates free iron during iron stress. Importantly, polyP is present in all cells and organisms and hence is likely to take on this crucial function in both prokaryotic and eukaryotic cells.
Beaufay, François ; Université de Liège - ULiège > Département des sciences de la vie > Centre d'Ingénierie des Protéines (CIP) ; Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA
Quarles, Ellen; Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA
Franz, Allison; Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA
Katamanin, Olivia; Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA
Wholey, Wei-Yun; Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA
Jakob, Ursula ; Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA ujakob@umich.edu ; Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, USA
Language :
English
Title :
Polyphosphate Functions In Vivo as an Iron Chelator and Fenton Reaction Inhibitor.
EMBO - European Molecular Biology Organization NIH - National Institutes of Health
Funding text :
This work was supported by NIH grants GM122506 to U.J. and an NIH T32 Career Training in the Biology of Aging grant to E.Q.; F.B. was funded by an EMBO long-term fellowship (ALTF 601-2016).
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