Benzene polyphosphates as tools for cell signalling: inhibition of inositol 1,4,5‐trisphosphate 5‐phosphatase and interaction with the PH domain of protein kinase Bα

Reference:

Mills, S. J., Vandeput, F., Trusselle, M. N., Safrany, S. T., Erneux, C. and Potter, B. V. L., 2008. Benzene polyphosphates as tools for cell signalling: inhibition of inositol 1,4,5‐trisphosphate 5‐phosphatase and interaction with the PH domain of protein kinase Bα. ChemBiochem, 9 (11), pp. 1757-1766.

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Official URL:

http://dx.doi.org/10.1002/cbic.200800104

Abstract

Novel benzene polyphosphates were synthesised as inositol polyphosphate mimics and evaluated against type-1 inositol 1,4,5-trisphosphate 5-phosphatase, which only binds soluble inositol polyphosphates, and against the PH domain of protein kinase B alpha (PKB alpha), which can bind both soluble inositol polyphosphates and inositol phospholipids. The most potent trisphosphate 5-phosphotase inhibitor is benzene 1,2,4-trisphosphote (2, IC50 of 14 mu m), a potential mimic of D-myo-inositol 1,4,5-trisphosphate, whereas the most potent tetrakisphosphote Ins(1,4,5)P, 5-phosphotase inhibitor is benzene 1,2,4,5-tetrakisphosphate, with an IC50 of 4 mu M. Biphenyl 2,3',4,5',6-pentakisphosphate (4) was the most potent inhibitor evaluated against type 1 Ins(1,4,5)P-3 5-phosphatase (IC50 of 1 mu M). All new benzene polyphosphates are resistant to dephosphorylation by type 1 Ins(1,4,5)P-3 5-phosphatose. Unexpectedly, all benzene polyphosphates studied bind to the PH domain of PKBa with apparent higher affinity than to type I Ins(1,4,5)P3 5-phosphatase. The most potent ligand for the PKBa PH domain, measured by inhibition of biotinylated diC(8)-PtdIns(3,4)P-2 binding, is biphenyl 2,3',4,5',6-pentakisphosphate (4, K-i = 27 nM). The approximately 80-fold enhancement of binding relative to parent benzene trisphosphate is explained by the involvement of a cation-pi interaction. These new molecular tools will be of potential use in structural and cell signalling studies.

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