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Mills SJ, Vandeput F, Trusselle MN, Safrany ST, Erneux C, Potter BV: 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 Balpha. Chembiochem. 2008 Jul 21;9(11):1757-66.
Novel benzene polyphosphates were synthesised as inositol polyphosphate mimics and evaluated against type-I inositol 1,4,5-trisphosphate 5-phosphatase, which only binds soluble inositol polyphosphates, and against the PH domain of protein kinase Balpha (PKBalpha), which can bind both soluble inositol polyphosphates and inositol phospholipids. The most potent trisphosphate 5-phosphatase inhibitor is benzene 1,2,4-trisphosphate (2, IC (50) of 14 microM), a potential mimic of D-myo-inositol 1,4,5-trisphosphate, whereas the most potent tetrakisphosphate Ins (1,4,5) P (3) 5-phosphatase inhibitor is benzene 1,2,4,5-tetrakisphosphate, with an IC (50) of 4 microM. Biphenyl 2,3',4,5',6-pentakisphosphate (4) was the most potent inhibitor evaluated against type I Ins (1,4,5) P (3) 5-phosphatase (IC (50) of 1 microM). All new benzene polyphosphates are resistant to dephosphorylation by type I Ins (1,4,5) P (3) 5-phosphatase. Unexpectedly, all benzene polyphosphates studied bind to the PH domain of PKBalpha with apparent higher affinity than to type I Ins (1,4,5) P (3) 5-phosphatase. The most potent ligand for the PKBalpha 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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