title: scyllo-inositol pentakisphosphate as an analogue of myo-inositol 1,3,4,5,6-pentakisphosphate: chemical synthesis, physicochemistry and biological applications.
abstract: 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.
authors.affiliation: Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, UK.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Riley
authors.forename: Melanie
authors.initials: M
authors.lastname: Trusselle
authors.forename: Paul
authors.initials: P
authors.lastname: Kuad
authors.forename: Michal
authors.initials: M
authors.lastname: Borkovec
authors.forename: Jaiesoon
authors.initials: J
authors.lastname: Cho
authors.forename: Jae H
authors.initials: JH
authors.lastname: Choi
authors.forename: Xun
authors.initials: X
authors.lastname: Qian
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Shears
authors.forename: Bernard
authors.initials: B
authors.lastname: Spiess
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
mesh_terms: 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
chemical_list: 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