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

Graeme Horne, Clarisse Maechling, Andrea Fleig, Masato Hirata, Reinhold Penner, Bernard Spiess, Barry V.L. Potter

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

D-6-Deoxy-myo-inositol 1,3,4,5-tetrakisphosphate [D-6-deoxy-Ins(1,3,4,5) P4] 3 is a novel deoxygenated analogue of D-myo-inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4] 2, a central and enigmatic molecule in the polyphosphoinositide pathway of cellular signalling. D-6-Deoxy-Ins(1,3,4,5)P4 is a moderate inhibitor of Ins(1,4,5)P 3 5-phosphatase [1.8μM] compared to Ins(1,3,4,5)P4 [0.15μM] and similar to that of L-Ins(1,3,4,5)P4 [1.8μM]. In displacement of [3H] Ins(1,4,5)P3 from the rat cerebellar Ins(1,4,5)P3 receptor, while slightly weaker [IC50=800nM] than that of D-Ins(1,3,4,5)P4 [IC50=220nM], 3 is less markedly different and again similar to that of L-Ins(1,3,4,5)P4 [IC50=660nM]. 3 is an activator of ICRAC 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 31P and 1H NMR titrations and were similar to those of Ins(1,3,4,5)P4 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)P4 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)P4 is crucial for its physicochemical behaviour and biological properties of this key inositol phosphate.

Original languageEnglish
Pages (from-to)1262-1270
Number of pages9
JournalBiochemical and Biophysical Research Communications
Volume320
Issue number4
DOIs
Publication statusPublished - Aug 6 2004

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this