scyllo-inositol pentakisphosphate as an analogue of myo-inositol 1,3,4,5,6-pentakisphosphate: chemical synthesis, physicochemistry and biological applications.
myo-Inositol 1,3,4,5,6-pentakisphosphate (Ins(1,3,4,5,6)P(5)), an inositol polyphosphate of emerging significance in cellular signalling, and its C-2 epimer scyllo-inositol pentakisphosphate (scyllo-InsP(5)) were synthesised from the same myo-inositol-based precursor. Potentiometric and NMR titrations show that both pentakisphosphates undergo a conformational ring-flip at higher pH, beginning at pH 8 for scyllo-InsP(5) and pH 9 for Ins(1,3,4,5,6)P(5). Over the physiological pH range, however, the conformation of the inositol rings and the microprotonation patterns of the phosphate groups in Ins(1,3,4,5,6)P(5) and scyllo-InsP(5) are similar. Thus, scyllo-InsP(5) should be a useful tool for identifying biologically relevant actions of Ins(1,3,4,5,6)P(5), mediated by specific binding sites, and distinguishing them from nonspecific electrostatic effects. We also demonstrate that, although scyllo-InsP(5) and Ins(1,3,4,5,6)P(5) are both hydrolysed by multiple inositol polyphosphate phosphatase (MINPP), scyllo-InsP(5) is not dephosphorylated by PTEN or phosphorylated by Ins(1,3,4,5,6)P(5) 2-kinases. This finding both reinforces the value of scyllo-InsP(5) as a biological control and shows that the axial 2-OH group of Ins(1,3,4,5,6)P(5) plays a part in substrate recognition by PTEN and the Ins(1,3,4,5,6)P(5) 2-kinases.
Riley
Andrew M
AM
Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, UK.
Trusselle
Melanie
M
Kuad
Paul
P
Borkovec
Michal
M
Cho
Jaiesoon
J
Choi
Jae H
JH
Qian
Xun
X
Shears
Stephen B
SB
Spiess
Bernard
B
Potter
Barry V L
BV
D007295:Inositol Phosphates / Q000138:chemical synthesis / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008968:Molecular Conformation; D051059:PTEN Phosphohydrolase / Q000737:chemistry; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000378:metabolism; D011199:Potentiometry / Q000379:methods; D018892:Proton-Motive Force; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D007295:Inositol Phosphates; C513275:scyllo-inositol pentakisphosphate; C013571:inositol pentaphosphate; D010744:Phosphoric Monoester Hydrolases; C064119:multiple inositol-polyphosphate phosphatase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human