D-6-Deoxy-myo-inositol 1,3,4,5-tetrakisphosphate, a mimic of d-myo-inositol 1,3,4,5-tetrakisphosphate: biological activity and pH-dependent conformational properties |
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Authors: | Horne Graeme Maechling Clarisse Fleig Andrea Hirata Masato Penner Reinhold Spiess Bernard Potter Barry V L |
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Institution: | Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK. |
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Abstract: | D-6-Deoxy-myo-inositol 1,3,4,5-tetrakisphosphate D-6-deoxy-Ins(1,3,4,5)P(4)] 3 is a novel deoxygenated analogue of D-myo-inositol 1,3,4,5-tetrakisphosphate Ins(1,3,4,5)P(4)] 2, a central and enigmatic molecule in the polyphosphoinositide pathway of cellular signalling. D-6-Deoxy-Ins(1,3,4,5)P(4) is a moderate inhibitor of Ins(1,4,5)P(3) 5-phosphatase 1.8microM] compared to Ins(1,3,4,5)P(4) 0.15microM] and similar to that of L-Ins(1,3,4,5)P(4) 1.8microM]. In displacement of (3)H] Ins(1,4,5)P(3) from the rat cerebellar Ins(1,4,5)P(3) receptor, while slightly weaker IC(50)=800nM] than that of D-Ins(1,3,4,5)P(4) IC(50)=220nM], 3 is less markedly different and again similar to that of L-Ins(1,3,4,5)P(4) IC(50)=660nM]. 3 is an activator of I(CRAC) when inward currents are measured in RBL-2H3-M1 cells using patch-clamp electrophysiological techniques with a facilitation curve different to that of Ins(1,3,4,5)P(4). Physicochemical properties were studied by potentiometric (31)P and (1)H NMR titrations and were similar to those of Ins(1,3,4,5)P(4) apart from the observation of a biphasic titration curve for the P1 phosphate group. A novel vicinal phosphate charge-induced conformational change of the inositol ring above pH 10 was observed for D-6-deoxy-Ins(1,3,4,5)P(4) that would normally be hindered because of the central stabilising role played by the 6-OH group in Ins(1,3,4,5)P(4). We conclude that the 6-OH group in Ins(1,3,4,5)P(4) is crucial for its physicochemical behaviour and biological properties of this key inositol phosphate. |
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Keywords: | Signal transduction Inositol phosphates 31P NMR Potentiometry Electrophysiology Structure-activity relationships IP3-kinase IP3 5-phosphatase |
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