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“Chelatable iron pool”: inositol 1,2,3-trisphosphate fulfils the conditions required to be a safe cellular iron ligand

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Abstract

Mammalian cells contain a pool of iron that is not strongly bound to proteins, which can be detected with fluorescent chelating probes. The cellular ligands of this biologically important “chelatable”, “labile” or “transit” iron are not known. Proposed ligands are problematic, because they are saturated by magnesium under cellular conditions and/or because they are not “safe”, i.e. they allow iron to catalyse hydroxyl radical formation. Among small cellular molecules, certain inositol phosphates (InsPs) excel at complexing Fe3+ in such a “safe” manner in vitro. However, we previously calculated that the most abundant InsP, inositol hexakisphosphate, cannot interact with Fe3+ in the presence of cellular concentrations of Mg2+. In this work, we study the metal complexation behaviour of inositol 1,2,3-trisphosphate [Ins(1,2,3)P 3], a cellular constituent of unknown function and the simplest InsP to display high-affinity, “safe”, iron complexation. We report thermodynamic constants for the interaction of Ins(1,2,3)P 3 with Na+, K+, Mg2+, Ca2+, Cu2+, Fe2+ and Fe3+. Our calculations indicate that Ins(1,2,3)P 3 can be expected to complex all available Fe3+ in a quantitative, 1:1 reaction, both in cytosol/nucleus and in acidic compartments, in which an important labile iron subpool is thought to exist. In addition, we calculate that the fluorescent iron probe calcein would strip Fe3+ from Ins(1,2,3)P 3 under cellular conditions, and hence labile iron detected using this probe may include iron bound to Ins(1,2,3)P 3. Therefore Ins(1,2,3)P 3 is the first viable proposal for a transit iron ligand.

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Acknowledgments

AD is grateful to the Biochemical Society for a bursary to attend the Harden Conference on Inositol Phosphates and Lipids. CB acknowledges the Karolinska Institutet and Novo Nordisk Foundation. NV is indebted to PEDECIBA-Química and ANII for a scholarship. The authors are grateful to Prof. Sung-Kee Chung (Pohang University of Science and Technology, Korea) for generously providing 1,2,3-InsP 3 standards and to Prof. Robin F. Irvine (University of Cambridge, UK) for encouraging discussions.

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Authors and Affiliations

  1. Cátedra de Química Inorgánica, Departamento Estrella Campos, Facultad de Química, Universidad de la República, CC 1157, Montevideo, Uruguay

    Nicolás Veiga, Julia Torres & Carlos Kremer

  2. School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, UK

    David Mansell & Sally Freeman

  3. Departamento de Química Inorgánica, Universidad de La Laguna, Tenerife, Canary Islands, Spain

    Sixto Domínguez

  4. Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, 171 76, Stockholm, Sweden

    Christopher J. Barker

  5. Cátedra de Inmunología, Facultad de Química/Ciencias, Universidad de la República, Avenida Alfredo Navarro 3051, CP 11600, Montevideo, Uruguay

    Alvaro Díaz

Authors
  1. Nicolás Veiga
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  2. Julia Torres
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  3. David Mansell
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  4. Sally Freeman
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  5. Sixto Domínguez
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  6. Christopher J. Barker
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  7. Alvaro Díaz
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  8. Carlos Kremer
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Corresponding authors

Correspondence to Alvaro Díaz or Carlos Kremer.

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Veiga, N., Torres, J., Mansell, D. et al. “Chelatable iron pool”: inositol 1,2,3-trisphosphate fulfils the conditions required to be a safe cellular iron ligand. J Biol Inorg Chem 14, 51–59 (2009). https://doi.org/10.1007/s00775-008-0423-2

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  • DOI: https://doi.org/10.1007/s00775-008-0423-2

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