Interaction of the Catalytic Domain of Inositol 1,4,5‐Trisphosphate 3‐Kinase A with Inositol Phosphate Analogues

Poinas, Alexandra; Backers, Katrien; Riley, Andrew M.; Mills, Stephen; Moreau, Colette; Potter, Barry V. L.; Erneux, Christophé

doi:10.1002/cbic.200400443

Cited by 13 publications

(19 citation statements)

References 50 publications

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“…In this case, the IC 50 and K i value are equivalent due to the low ATP concentrations in the assay. The K i of 18 M (Table 1) is somewhat higher than the values reported by other authors (21,22).…”

Section: Tnp Is a Selective Inhibitor Of The Ip6ks In Vitro And In Vivo-contrasting

confidence: 55%

Characterization of a Selective Inhibitor of Inositol Hexakisphosphate Kinases

Padmanabhan

Dollins

Fridy

et al. 2009

Journal of Biological Chemistry

108

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Inositol hexakisphosphate kinases (IP6Ks) phosphorylate inositol hexakisphosphate (InsP 6 ) to yield 5-diphosphoinositol pentakisphosphate (5-[PP]-InsP 5 or InsP 7 ). In this study, we report the characterization of a selective inhibitor, N 2 -(m-(trifluoromethy)lbenzyl) N 6 -(p-nitrobenzyl)purine (TNP), for these enzymes. TNP dose-dependently and selectively inhibited the activity of IP6K in vitro and inhibited InsP 7 and InsP 8 synthesis in vivo without affecting levels of other inositol phosphates. TNP did not inhibit either human or yeast Vip/PPIP5K, a newly described InsP 6 /InsP 7 1/3-kinase. Overexpression of IP6K1, -2, or -3 in cells rescued TNP inhibition of InsP 7 synthesis. TNP had no effect on the activity of a large number of protein kinases, suggesting that it is selective for IP6Ks. TNP reversibly reduced InsP 7 /InsP 8 levels. TNP in combination with genetic studies was used to implicate the involvement of two pathways for synthesis of InsP 8 in yeast. TNP induced a fragmented vacuole phenotype in yeast, consistent with inhibition of Kcs1, a Saccharomyces cerevisiae IP6K. In addition, it also inhibited insulin release from Min6 cells in a dose-dependent manner further implicating InsP 7 in this process. TNP thus provides a means of selectively and rapidly modulating cellular InsP 7 levels, providing a new and versatile tool to study the biological function and metabolic relationships of inositol pyrophosphates.Inositol(1,4,5)trisphosphate (Ins(1,4,5)P 3 ) 2 is the cytosolic product of inositol phospholipid-specific phospholipase Cs and serves multiple biological functions. In higher eukaryotes, it regulates Ca 2ϩ release from intracellular stores via binding to Ins(1,4,5)P 3 -specific receptors located in the endoplasmic reticulum. In addition, in Saccharomyces cerevisiae and all other eukaryotes that have been studied, Ins(1,4,5)P 3 also undergoes complex metabolism to generate a series of inositol polyphosphates with diverse functions (1, 2). Inositol hexakisphosphate (InsP 6 ) can be synthesized in inositol phospholipid-specific phospholipase C/Ins(1,4,5)P 3 -mediated pathways in most, if not all, eukaryotes. InsP 6 is further metabolized by the inositol hexakisphosphate kinases (IHPKs or IP6Ks), which add a pyrophosphate moiety at the 5-position to generate 5-[PP]-InsP 5 or 5-InsP 7 . Dictyostelium discoideum and S. cerevisiae, each possess one IP6K gene product designated Kcs1 in yeast (3, 4). In mammals, three IP6Ks have been identified (5, 6). In addition, a second InsP 6 /5-InsP 7 kinase, designated Vip/PPIP5K, has been identified in yeast (7) and mammalian cells (8,9). This kinase is distinct from IP6K/Kcs1 in that it phosphorylates the 1/3-position of InsP 6 and 5-[PP]-InsP 5 (10).Insights into the biological functions of inositol pyrophosphates have come from genetic studies in yeast and by manipulating expression of inositol polyphosphate kinases in mammalian cells. More recently, yeast mutants failing to synthesize inositol pyro phosphate molecules have been found to be impaired in s...

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Section: Tnp Is a Selective Inhibitor Of The Ip6ks In Vitro And In Vivo-contrasting

confidence: 55%

Characterization of a Selective Inhibitor of Inositol Hexakisphosphate Kinases

Padmanabhan

Dollins

Fridy

et al. 2009

Journal of Biological Chemistry

108

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“…Indeed, several groups have identified small-molecule ITPK inhibitors. Some show high ITPK-selectivity over IPMK33, 109–112.…”

Section: Therapeutic Relevancementioning

confidence: 99%

Regulation of immune cell development through soluble inositol-1,3,4,5-tetrakisphosphate

2010

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Preface The membrane lipid phosphatidylinositol(3,4,5)trisphosphate (PtdInsP3) regulates membrane receptor signalling in many cells, including immunoreceptor signalling. Here, we review recent data that have indicated essential functions for the soluble PtdInsP3 analogue inositol(1,3,4,5)tetrakisphosphate (InsP4) in T cell, B cell and neutrophil development and function. Decreased InsP4 production in immunocytes causes immunodeficiency in mice and might contribute to inflammatory vasculitis in Kawasaki disease in humans. InsP4-producing kinases could therefore provide attractive drug targets for inflammatory and infectious diseases.

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“…18 F-FDMCI-3′-phosphate is not a substrate for the inositol transporter, and being very polar, cannot cross the cell membrane, and thus will be trapped inside the cell. 14 …”

Section: Resultsmentioning

confidence: 99%

“…11 More recently, Poinas et al studied the interaction of the catalytic domain of IP 3 -3KA with several inositol phosphate analogues and found that removal of the 2′-OH was tolerated and would still allow for substrate activity. 12 …”

Section: Introductionmentioning

confidence: 99%

Design and synthesis of an inositol phosphate analog based on computational docking studies

Peng¹,

Maxwell²,

Sun³

et al. 2014

Tetrahedron

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A virtual library of 54 inositol analog mimics of In(1,4,5)P3 has been docked, scored, and ranked within the binding site of human inositol 1,4,5-trisphosphate 3-kinase A (IP3-3KA). Chemical synthesis of the best scoring structure that also met distance criteria for 3′-OH to -P in Phosphate has been attempted along with the synthesis of (1S,2R,3S,4S)-3-fluoro-2,4-dihydroxycyclohexanecarboxylic acid as an inositol analog, useful for non-invasive visualization and quantitation of IP3-3KA enzymatic activity

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Interaction of the Catalytic Domain of Inositol 1,4,5‐Trisphosphate 3‐Kinase A with Inositol Phosphate Analogues

Cited by 13 publications

References 50 publications

Characterization of a Selective Inhibitor of Inositol Hexakisphosphate Kinases

Characterization of a Selective Inhibitor of Inositol Hexakisphosphate Kinases

Regulation of immune cell development through soluble inositol-1,3,4,5-tetrakisphosphate

Design and synthesis of an inositol phosphate analog based on computational docking studies

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