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. 2012 Nov 28;48(92):11292-4.
doi: 10.1039/c2cc36044f.

First synthetic analogues of diphosphoinositol polyphosphates: interaction with PP-InsP5 kinase

Andrew M Riley  1 , Huanchen Wang, Jeremy D Weaver, Stephen B Shears, Barry V L Potter
Affiliations

First synthetic analogues of diphosphoinositol polyphosphates: interaction with PP-InsP5 kinase

Andrew M Riley et al. Chem Commun (Camb). .

Abstract

We synthesised analogues of diphosphoinositol polyphosphates (PP-InsPs) in which the diphosphate is replaced by an α-phosphonoacetic acid (PA) ester. Structural analysis revealed that 5-PA-InsP(5) mimics 5-PP-InsP(5) binding to the kinase domain of PPIP5K2; both molecules were phosphorylated by the enzyme. PA-InsPs are promising candidates for further studies into the biology of PP-InsPs.

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Figures

Fig. 1
Fig. 1. (a) Origin of diphosphoinositol polyphosphates. IP5K, inositol pentakisphosphate 2-kinase; IP6K, inositol hexakisphosphate 5-kinase; PPIP5K, diphosphoinositol pentakisphosphate kinase. (b) Structures of phosphonoacetic acid ester (PA) analogues 1, 2 and 3. Bn = benzyl.
Scheme 1
Scheme 1. Synthesis of PA analogues 1, 2 and 3. Reagents and conditions: a. BnBr, NaH, DMF, 55%; b. (BnO)2P(O)CH2COOH, DCC, CH2Cl2, 73%; c. (BnO)2P(O)CH2COOH, EDAC, DMAP, CH2Cl2, 95%; d. TFA, H2O, 5 min, 50–62%; e. (i) (BnO)2PNPr2 i, 5-phenyl-1H-tetrazole, CH2Cl2; (ii) mCPBA, CH2Cl2, 84–95%; f. H2, Pd(OH)2/C, MeOH, H2O, 92%; g. H2, Pd(OH)2/C, MeOH, H2O, 50 psi, 79%; h. H2, Pd(OH)2/C, MeOH, aqueous triethylammonium bicarbonate, 79%. Bn = benzyl.
Fig. 2
Fig. 2. Inhibition of human PPIP5K2 by analogues 1, 2 and 3 in the presence of 100 nM 1,5-[PP]2-InsP4.
Fig. 3
Fig. 3. Binding of 5-PA-InsP5 (2) to human PPIP5K2KD (a–c) and phosphorylation of 2 by PPIP5K2KD (d). (a) 5-PA-InsP5 (2, ball-and-stick model) and its interacting residues (stick model) for hPPIP5K2 are shown in light blue for carbon, blue for nitrogen, orange and red for phosphate groups. Residues that make contacts with 5-PP-InsP5 (green stick) are also shown in green carbon. Magnesium atoms are shown as spheres. C-4 and C-5 in the inositol ring are labelled. (b) Residues that interact with PA or PP are shown. Bond distances (dashed lines) are denoted in Å. (c) Key catalytic residues are shown in stick model. Inositol phosphates and nucleotide cofactors are shown in ball-and-stick model. Colours are as (a). Also shown are catalytic magnesium atoms (magenta spheres). C-1 of the inositol ring is labelled. Bond distances (dashed lines) are denoted in Å. (d) Phosphorylation of 5-PA-InsP5 by PPIP5K2KD.
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