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3‐Hydroxybenzene 1,2,4‐Trisphosphate, a Novel Second Messenger Mimic and unusual Substrate for Type‐I myo ‐Inositol 1,4,5‐Trisphosphate 5‐Phosphatase: Synthesis and Physicochemistry
Author(s) -
Mills Stephen J.,
Dozol Hélène,
Vandeput Fabrice,
Backers Katrien,
Woodman Timothy,
Erneux Christophe,
Spiess Bernard,
Potter Barry V. L.
Publication year - 2006
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200600125
Subject(s) - chemistry , inositol , dephosphorylation , phosphatase , phosphate , stereochemistry , inositol phosphate , phosphorylation , biochemistry , receptor
Abstract 3‐Hydroxybenzene 1,2,4‐trisphosphate 4 is a new myo ‐inositol 1,4,5‐trisphosphate analogue based on the core structure of benzene 1,2,4‐trisphosphate 2 with an additional hydroxyl group at position‐3, and is the first noninositol based compound to be a substrate for inositol 1,4,5‐trisphosphate 5‐phosphatase. In physicochemical studies on 2 , when three equivalents of protons were added, the 31 P NMR spectrum displayed monophasic behaviour in which phosphate‐1 and phosphate‐2 behaved independently in most of the studied pH range. For compound 4 , phosphate‐2 and phosphate‐4 interacted with the 3‐OH group, which does not titrate at physiological pH, displaying complex biphasic behaviour which demonstrated co‐operativity between these groups. Phosphate‐1 and phosphate‐2 strongly interacted with each other and phosphate‐4 experienced repulsion because of the interaction of the 3‐OH group. Benzene 1,2,4‐trisphosphate 2 is resistant to inositol 1,4,5‐trisphosphate type I 5‐phosphatase catalysed dephosphorylation. However, surprisingly, 3‐hydroxybenzene 1,2,4‐trisphosphate 4 was dephosphorylated by this 5‐phosphatase to give the symmetrical 2,3‐dihydroxybenzene 1,4‐bisphosphate 16 . The extra hydroxyl group is shown to form a hydrogen bond with the vicinal phosphate groups at −15 °C, and 1 H NMR titration of the ring and hydroxyl protons in 4 shows the OH proton to be strongly stabilized as soon as the phosphate groups are deprotonated. The effect of the phenolic 3‐OH group in compound 4 confirms a critical role for the 6‐OH group of the natural messenger in the dephosphorylation mechanism that persists even in radically modified analogues.