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myo -Inositol 1,2,3-trisphosphate [Ins(1,2,3)P 3 ], a component in mammalian cells, possesses the correct chemical properties of an intracellular iron transit ligand. Here we have examined the conformation of the Ins(1,2,3)P 3 –Fe 3+ complex. The synthesis and antioxidant properties of 4,6-carbonate- myo -inositol 1,2,3,5-tetrakisphosphate [4,6-carbonate Ins(1,2,3,5)P 4 ], which is locked in the unstable penta-axial chair conformation and 1,2,3-trisphosphoglycerol, a flexible acyclic analogue of Ins(1,2,3)P 3 , are reported. 4,6-Carbonate Ins(1,2,3,5)P 4 caused complete inhibition of iron-catalysed hydroxyl radical (HO ) formation at 100 μM, thereby resembling Ins(1,2,3)P 3 and supporting a penta-axial chair binding conformation. In contrast, 1,2,3-trisphosphoglycerol was shown to have incomplete antioxidant properties. In support of experimental observations, we have applied high-level density functional calculations to the binding of Ins(1,2,3)P 3 to iron. This study provides evidence that Fe 3+ binds tightly to the less stable penta-axial conformation of Ins(1,2,3)P 3 using terminal and bridging phosphate oxygens, thought to also contain a tightly bound water molecule or hydroxyl ligand in the complex. |
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