2-Hydroxyethyl-alpha-D-glucopyranoside-2,3',4'-trisphosphate, a novel, metabolically resistant, adenophostin A and myo-inositol-1,4,5-trisphosphate analogue, potently interacts with the myo-inositol-1,4,5-trisphosphate receptor
| Autor: | R A, Wilcox, C, Erneux, W U, Primrose, R, Gigg, S R, Nahorski |
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| Rok vydání: | 1995 |
| Předmět: |
Adenosine
Ion Transport Inositol Polyphosphate 5-Phosphatases Molecular Conformation Receptors Cytoplasmic and Nuclear Inositol 1 4 5-Trisphosphate Phosphoric Monoester Hydrolases Recombinant Proteins Neuroblastoma Phosphotransferases (Alcohol Group Acceptor) Glucosides Tumor Cells Cultured Humans Inositol 1 4 5-Trisphosphate Receptors Calcium Computer Simulation Calcium Channels |
| Zdroj: | Molecular pharmacology. 47(6) |
| ISSN: | 0026-895X |
| Popis: | The novel, synthetic, adenophostin A analogue 2-hydroxyethyl-alpha-D-glucopyranoside-2,3',4'-trisphosphate [Glu(2,3',4')P3] was synthesized to probe the structure-activity relationship at the D-myo-inositol-1,4,5-trisphosphate [Ins(1,4,5)P3] receptor [Ins(1,4,5)P3R]. This study was stimulated by the recent observation that the fungal isolates adenophostins A and B were very potent, metabolically resistant, Ins(1,4,5)P3R agonists [J. Biol. Chem. 269:369-372 (1994)]. Gluc(2,3',4')P3 can be visualized as a truncated version of adenophostin A, in which the 2'- and 3'-carbons of the ribose ring, with their terminal phosphate groups, are retained and the remainder of the adenosine residue is excised. Gluc(2,3',4')P3 specifically displaced [3H]Ins(1,4,5)P3 from pig cerebellar Ins(1,4,5)P3 binding sites, with an affinity (IC50 = 130 nM) only 5-fold weaker than that of Ins(1,4,5)P3 (IC50 = 27 nM). Gluc(2,3',4')P3 was also a full agonist for Ca2+ release, being only 10-12-fold less potent than Ins(1,4,5)P3 in saponin-permeabilized SH-SY5Y neuroblastoma cells [EC50 = 647 nM; Ins(1,4,5)P3 EC50 = 52 nM] and Madin-Darby canine kidney cells [EC50 = 2484 nM; Ins(1,4,5)P3 EC50 = 247 nM]. Gluc(2,3',4')P3 did not significantly interact with recombinant Ins(1,4,5)P3 3-kinase and 5-phosphatase enzymes and was also poorly metabolized by saponin-permeabilized SH-SY5Y cells. However, Gluc(2,3',4')P3 was a considerably weaker ligand (approximately 500-fold) and agonist (approximately 1000-fold) than adenophostin A, suggesting that the partial excision of the adenosine residue compromised structural motifs that have favorable interactions with the Ins(1,4,5)P3R. Indeed, molecular dynamics simulations revealed that the potencies of the three compounds show a correlation with the relative distance of the two vicinal ring phosphates from the remaining phosphate. Gluc(2,3',4')P3, with its alpha-glucoside ring, is the first synthetic Ins(1,4,5)P3 analogue that is not structurally based on a phosphorylated inositol isomer and that exhibits potent activity at the Ins(1,4,5)P3R. This, combined with the metabolic resistance of Gluc(2,3',4')P3, thus affords a novel approach for the investigation of the cellular role of Ins(1,4,5)P3 and its receptor. |
| Databáze: | OpenAIRE |
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