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.
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.
Horne
Graeme
G
Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK.
Maechling
Clarisse
C
Fleig
Andrea
A
Hirata
Masato
M
Penner
Reinhold
R
Spiess
Bernard
B
Potter
Barry V L
BV
D015220:Calcium Channels / Q000737:chemistry* / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007295:Inositol Phosphates / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism; D000072181:Inositol Polyphosphate 5-Phosphatases; D008968:Molecular Conformation; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007295:Inositol Phosphates; D018160:Receptors, Cytoplasmic and Nuclear; C081655:inositol-1,3,4,5-tetrakisphosphate; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases