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.

Inframolecular acid–base and coordination properties towards Na+and Mg2+of myo-inositol 1,3,4,5,6-pentakisphosphate: a structural approach to biologically relevant species

“…The signal broadening in the Ins(1,3,4,5,6) P 5 31 P NMR spectra has been previously related to the conformational change of this ligand in solution. 16 Under our experimental conditions, the pH range associated with this phenomenon is 10.4–11.7 (see Fig. S1a†).…”

Purification, Sequencing, and Molecular Identification of a Mammalian PP-InsP5 Kinase That Is Activated When Cells Are Exposed to Hyperosmotic Stress

“…York and colleagues (33) (35). Recombinant human Ins(1,3,4,5,6)P 5 2-kinase was prepared as described previously (37).…”

The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances inmyo‐Inositol Chemistry)

“…[11] Some of these phosphorylated inositol isomers have been chemically synthesised and tested in assays against various enzymes and receptors to find possible biological roles.[e.g. 32,80,84,164] Obviously, such derivatives with different stereochemistry or regiochemistry of substitution can merely just act on systems controlled by myo-inositol derivatives, but the hope would be to find unique activities. The higher inositol polyphosphate field is an emerging area of likely seminal importance in signaling, largely unexplored structurally, and PP-InsP binding sites could be attractive new drug targets.…”

“…[31] The syntheses of myo-inositol 1,3,4,5,6-pentakisphosphate and its C2 epimer scyllo-inositol pentakisphosphate starting from myo-inositol orthoformate have been described. [32] …”

“…[81] scyllo-Inositol 1,2,3,4,5-pentakisphosphate (101) is hydrolyzed by multiple inositol polyphosphate phosphatase but is not dephosphorylated by PTEN or phosphorylated at the 6-position (the equivalent of the myoinositol 2-position) by pentakisphosphate 2-kinases. [32] 5 D-chiro-Inositol…”