Intracellular recognition sites for inositol 1,4,5-triphosphate and inositol 1,3,4,5-tetrakisphosphate

Challiss, R. A. John; Safrany, Stephen T.; Potter, Barry V. L.; Nahorski, Stefan R.

doi:10.1042/bst0190888

Cited by 9 publications

(1 citation statement)

References 16 publications

(27 reference statements)

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“…On the basis of the observation that affinity for 5-phosphatase is increased following phosphorothioate substitution, we proposed that L-Ins(l,4,5)PS3 would be a potent and selective 5-phosphatase inhibitor (Challiss et al, 1991). As L-Ins( 1,4,5)P3 is recognized well by 5-phosphatase and poorly by both the Ins(l,4,5)P3 receptor and 3-kinase, phosphorothioate substitution would be expected to decrease affinity for the Ins(l,4,5)P3 receptor and 3-kinase, while greatly increasing affinity for 5-phosphatase.…”

Section: Resultsmentioning

confidence: 99%

Design of Potent and Selective Inhibitors of myo-Inositol 1,4,5-Trisphosphate 5-Phosphatase

Safrany¹,

Mills²,

Liu³

et al. 1994

Biochemistry

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The interactions of synthetic analogues of D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] with the Ins(1,4,5)P3 receptor in permeabilized SH-SY5Y cells and with two key metabolic enzymes, Ins(1,4,5)P(3)3-kinase from a supernatant preparation of rat brain homogenates and Ins(1,4,5)P(3)5-phosphatase from human erythrocyte ghosts, have been examined. L-chiro-Inositol 2,3,5-trisphosphorothioate [L-chiro-Ins(2,3,5)PS3], which we have previously identified as a partial agonist at the Ins(1,4,5)P3 receptor [Safrany, S. T., Wilcox, R. A., Liu, C., Dubreuil, D., Potter, B. V. L., & Nahorski S. R. (1993) Mol. Pharmacol. 43, 499-503], is identified as the most potent 5-phosphatase inhibitor yet described (inhibiting dephosphorylation of [3H]Ins(1,4,5)P3 with Ki = 230nM). L-chiro-Ins(2,3,5)PS3 was also found to be the most potent small-molecule inhibitor of 3-kinase (Ki = 820 nM). The properties of three novel, potent, and selective inhibitors of 5-phosphatase are described. L-myo-Inositol 1,4,5-trisphosphorothioate inhibited 5-phosphatase with Ki = 430 nM, showing 250-fold selectivity over 3-kinase (Ki = 108 microM); myo-inositol 1,3,5-trisphosphorothioate inhibited 5-phosphatase with 475-fold selectivity over 3-kinase (Ki = 520 nM and 247 microM, respectively). The most potent, selective inhibitor of 5-phosphatase was L-chiro-inositol 1,4,6-trisphosphorothioate [L-chiro-Ins(1,4,6)PS3]. L-chiro-Ins(1,4,6)PS3 inhibited 5-phosphatase with Ki = 300 nM and did not interact with the Ins(1,4,5)P3 receptor or 3-kinase at doses tested. These studies, therefore, identify a highly potent and selective inhibitor of 5-phosphatase, which should be considered the tool of choice when inhibiting this enzyme in a broken cell or cell-free system.

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Section: Resultsmentioning

confidence: 99%

Design of Potent and Selective Inhibitors of myo-Inositol 1,4,5-Trisphosphate 5-Phosphatase

Safrany¹,

Mills²,

Liu³

et al. 1994

Biochemistry

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Die Chemie der Inositlipid‐vermittelten zellulären Signalübertragung

Potter

Lampe

1995

Angewandte Chemie

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Vor etwas mehr als einem Jahrzehnt berichteten Michael Berridge und seine Mitarbeiter in Nature: micromolar concentrations of Ins(1,4,5)P3 (1D‐myo‐inositol 1,4,5‐trisphosphate) release Ca2+ from a non‐mitochondrial intra‐cellular Ca2+ store in pancreatic acinar cells. Our results strongly suggest that this is the same Ca2+ store that is released by acetylcholine”︁. Mit der Entdeckung eines niedermolekularen sekundären Botenstoffs, der die räumlich getrennten Ereignisse der Aktivierung von Rezeptoren an der Zelloberfläche und der intrazellulären Ca2+ ‐Mobilisierung verbindet, wurde eine neue Ära auf dem Gebiet der Signalvermittlung eingeleitet und eine Renaissance der Inosit‐und Inositphosphatchemie stimuliert. Die Synthese von Inositpolyphosphaten bringt mehrere Probleme mit sich: die regiospezifische Einführung von Schutzgruppen am Inositring, die Racematspaltung der resultierenden Zwischenprodukte, die Phosphorylierung des Polyols, die Entfernung aller Phosphat‐Schutzgruppen unter Vermeidung einer gleichzeitigen Wanderung von Phosphatgruppen sowie die Reinigung des wasserlöslichen Ziel‐Polyanions. Mit der Lösung dieser Probleme in den letzten Jahren ist es jetzt möglich, über die Synthese von natürlichen Inositphosphaten hinaus (von denen ständig mehr gefunden werden) zur Entwicklung von chemisch modifizierten Inositphosphat‐Analoga überzugehen, mit der Aussicht, Enzyminhibitoren, zweckmäßig modifizierte Rezeptorliganden und ‐antagonisten sowie vielleicht sogar Therapeutica für den pharmakologischen Eingriff in Signalübertragungsbahnen zu entwickeln.

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Chemistry of Inositol Lipid Mediated Cellular Signaling

Potter

Lampe

1995

Angew. Chem. Int. Ed. Engl.

311

230

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It is now slightly more than a decade since Michael Berridge and his collaborators reported in Nuturr *'. . . micromolar concentrations of Ins(1,4.5)P3 ( 1~-uiJwinositol I ,4,5-trisphosphate) release Ca2 + from a non-mitochondria1 intraceIIuIar Ca'+ store in pancreatic acinar cells. Our results strongly suggest that this IS the same Ca" store that is released by acetylcholine". This observation ushered in a new era in the field of signal transduction with the discovery of a small-molecule second messenger linking the spatially separated events of cell surface receptor activation and intracellular Ca" mobilization. This event, which has spawned what is now one of the most active fields of current biology, also stimulated a renaissance in inositol and inositol phosphate chemistry. The synthesis of inositol polyphosphates presents a number of problems: the regiospecific protection of inositol and the optical resolution of the resulting precursors, the phosphorylation of the polyol, removal of all phosphate protecting groups without phosphate migration, and finally the purification of the water-soluble target polyanion. With the solution of these problems over the last few years it is now possible to look beyond the synthesis of naturally occurring inositol polyphosphates, whose number has been steadily increasing. to the design of chemically modified inositol phosphate analogues with the prospect of developing enzyme inhibitors, rationally modified receptor ligands and antagonists. and perhaps, through pharmacological intervention in signal transduction pathways, even the therapeutical agents of the future.

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Intracellular recognition sites for inositol 1,4,5-triphosphate and inositol 1,3,4,5-tetrakisphosphate

Cited by 9 publications

References 16 publications

Design of Potent and Selective Inhibitors of myo-Inositol 1,4,5-Trisphosphate 5-Phosphatase

Design of Potent and Selective Inhibitors of myo-Inositol 1,4,5-Trisphosphate 5-Phosphatase

Die Chemie der Inositlipid‐vermittelten zellulären Signalübertragung

Chemistry of Inositol Lipid Mediated Cellular Signaling

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