Polyphosphate Functions <italic toggle="yes">In Vivo</italic> as an Iron Chelator and Fenton Reaction Inhibitor

ABSTRACT 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 (...

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Autores principales:	François Beaufay, Ellen Quarles, Allison Franz, Olivia Katamanin, Wei-Yun Wholey, Ursula Jakob
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	chelator cisplatin iron regulation oxidative damage polyphosphate stress response Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/8bf01c8de1334955bd33759e52457c27
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spelling	oai:doaj.org-article:8bf01c8de1334955bd33759e52457c272021-11-15T15:56:44ZPolyphosphate Functions <italic toggle="yes">In Vivo</italic> as an Iron Chelator and Fenton Reaction Inhibitor10.1128/mBio.01017-202150-7511https://doaj.org/article/8bf01c8de1334955bd33759e52457c272020-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01017-20https://doaj.org/toc/2150-7511ABSTRACT 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.François BeaufayEllen QuarlesAllison FranzOlivia KatamaninWei-Yun WholeyUrsula JakobAmerican Society for Microbiologyarticlechelatorcisplatiniron regulationoxidative damagepolyphosphatestress responseMicrobiologyQR1-502ENmBio, Vol 11, Iss 4 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	chelator cisplatin iron regulation oxidative damage polyphosphate stress response Microbiology QR1-502
spellingShingle	chelator cisplatin iron regulation oxidative damage polyphosphate stress response Microbiology QR1-502 François Beaufay Ellen Quarles Allison Franz Olivia Katamanin Wei-Yun Wholey Ursula Jakob Polyphosphate Functions <italic toggle="yes">In Vivo</italic> as an Iron Chelator and Fenton Reaction Inhibitor
description	ABSTRACT 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.
format	article
author	François Beaufay Ellen Quarles Allison Franz Olivia Katamanin Wei-Yun Wholey Ursula Jakob
author_facet	François Beaufay Ellen Quarles Allison Franz Olivia Katamanin Wei-Yun Wholey Ursula Jakob
author_sort	François Beaufay
title	Polyphosphate Functions <italic toggle="yes">In Vivo</italic> as an Iron Chelator and Fenton Reaction Inhibitor
title_short	Polyphosphate Functions <italic toggle="yes">In Vivo</italic> as an Iron Chelator and Fenton Reaction Inhibitor
title_full	Polyphosphate Functions <italic toggle="yes">In Vivo</italic> as an Iron Chelator and Fenton Reaction Inhibitor
title_fullStr	Polyphosphate Functions <italic toggle="yes">In Vivo</italic> as an Iron Chelator and Fenton Reaction Inhibitor
title_full_unstemmed	Polyphosphate Functions <italic toggle="yes">In Vivo</italic> as an Iron Chelator and Fenton Reaction Inhibitor
title_sort	polyphosphate functions <italic toggle="yes">in vivo</italic> as an iron chelator and fenton reaction inhibitor
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/8bf01c8de1334955bd33759e52457c27
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Polyphosphate Functions <italic toggle="yes">In Vivo</italic> as an Iron Chelator and Fenton Reaction Inhibitor

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