Fluorescent probe: complexation of Fe3+with the myo-inositol 1,2,3-trisphosphate motif

David Mansell, Nicholas Rattray, Laura L. Etchells, Carl H. Schwalbe, Alexander J. Blake, Elena V. Bichenkova, Richard A. Bryce, Christopher J. Barker, Alvaro Diaz, Carlos Kremer, Sally Freeman

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Abstract

Natural myo-inositol phosphate antioxidants containing the 1,2,3-trisphosphate motif bind Fe3+ in the unstable penta-axial conformation.

The natural product myo-inositol 1,2,3-trisphosphate (1)1 (Ins(1,2,3)P3, cellular concentration ≤ 10 μM1) is a potent iron-chelator (apparent Ki = 9.0 × 10−19 M) and antioxidant, completely inhibiting iron-catalysed hydroxyl radical (HO˙) formation.2,3 Our recent potentiometric studies demonstrate that, unlike the more abundant myo-inositol hexakisphosphate (InsP6≈ 20 μM4), Ins(1,2,3)P3 fulfils the requirements of a safe, low molecular weight biological Fe3+ shuttle.5,6 Under conditions of excess Mg2+ (e.g. cytosolic and nuclear regions of mammalian cells), a negligible proportion of InsP6 is bound to Fe3+.7 In contrast, Fe3+ remains fully complexed with Ins(1,2,3)P3, both under Mg2+-rich conditions and in acidic, Ca2+-rich media such as in lysosomes.5 It was also predicted that iron bound to Ins(1,2,3)P3 must be Fe3+, since its affinity for Fe2+ is not high enough to allow interaction in the presence of excess cellular Mg2+. Although the biological relevance of Ins(1,2,3)P3 binding to iron is clear, the structure of its complex is uncertain and forms the subject of this paper. We have previously shown that the crystal structure of cyclohexylammonium Ins(1,2,3)P3 adopted the expected stable penta-equatorial chair conformation (1A).8 Here using density functional calculations at the UB3LYP/6-31+G* level,9 we have modelled 1 as the hexamethyl phosphoester, to represent protonation and counterion/solvent screening effects. From the optimal geometries, we have estimated that 1A is 8 kcal mol−1 more favourable in energy than the penta-axial conformation 1B (Scheme 1). This energetic preference increases to 30 kcal mol−1 for the hexaanionic forms of 1A and 1B.
Original languageEnglish
Pages (from-to)5161-5163
Number of pages3
JournalChemical Communications
Issue number41
DOIs
Publication statusPublished - 29 Sep 2008
Externally publishedYes

Keywords

  • fluorescent probe
  • ferric ion
  • fluorescent dye

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    Mansell, D., Rattray, N., Etchells, L. L., Schwalbe, C. H., Blake, A. J., Bichenkova, E. V., Bryce, R. A., Barker, C. J., Diaz, A., Kremer, C., & Freeman, S. (2008). Fluorescent probe: complexation of Fe3+with the myo-inositol 1,2,3-trisphosphate motif. Chemical Communications, (41), 5161-5163. https://doi.org/10.1039/B809238A