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(searched for: doi:10.1042/bss0740211)
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, Miranda S. Wilson, Verena B. Eisenbeis, Robert K. Harmel, Esther Riemer, Thomas M. Haas, Christopher Wittwer, Nikolaus Jork, Chunfang Gu, , et al.
Published: 27 November 2020
Nature Communications, Volume 11, pp 1-12; https://doi.org/10.1038/s41467-020-19928-x

Abstract:
The analysis ofmyo-inositol phosphates (InsPs) andmyo-inositol pyrophosphates (PP-InsPs) is a daunting challenge due to the large number of possible isomers, the absence of a chromophore, the high charge density, the low abundance, and the instability of the esters and anhydrides. Given their importance in biology, an analytical approach to follow and understand this complex signaling hub is desirable. Here, capillary electrophoresis (CE) coupled to electrospray ionization mass spectrometry (ESI-MS) is implemented to analyze complex mixtures of InsPs and PP-InsPs with high sensitivity. Stable isotope labeled (SIL) internal standards allow for matrix-independent quantitative assignment. The method is validated in wild-type and knockout mammalian cell lines and in model organisms. SIL-CE-ESI-MS enables the accurate monitoring of InsPs and PP-InsPs arising from compartmentalized cellular synthesis pathways, by feeding cells with either [13C6]-myo-inositol or [13C6]-D-glucose. In doing so, we provide evidence for the existence of unknown inositol synthesis pathways in mammals, highlighting the potential of this method to dissect inositol phosphate metabolism and signalling.
Published: 13 July 2018
Journal of Neuroscience, Volume 38, pp 7409-7419; https://doi.org/10.1523/JNEUROSCI.1165-18.2018

Abstract:
Inositol hexakisphosphate kinases (IP6Ks) regulate various biological processes. Among pyrophosphates generated by IP6Ks, diphosphoinositol pentakisphosphate (IP7), and bis-diphosphoinositol tetrakisphosphate have been extensively characterized. IP7 is produced in mammals by a family of inositol hexakisphosphate kinases, IP6K1, IP6K2, and IP6K3, which have distinct biological functions. We report that IP6K2 binds protein 4.1.N with high affinity and specificity. Nuclear translocation of 4.1N, which is required for its principal functions, is dependent on IP6K2. Both of these proteins are highly expressed in granule cells of the cerebellum where their interaction regulates Purkinje cell morphology and cerebellar synapses. The deletion of IP6K2 in male/female mice elicits substantial defects in synaptic influences of granule cells upon Purkinje cells as well as notable impairment of locomotor function. Moreover, the disruption of IP6K2–4.1N interactions impairs cell viability. Thus, IP6K2 and its interaction with 4.1N appear to be major determinants of cerebellar disposition and psychomotor behavior.
Swarna Gowri Thota,
Published: 13 August 2015
Journal of Biosciences, Volume 40, pp 593-605; https://doi.org/10.1007/s12038-015-9549-x

Abstract:
Inositol pyrophosphates are water soluble derivatives of inositol that contain pyrophosphate or diphosphate moieties in addition to monophosphates. The best characterised inositol pyrophosphates, are IP7 (diphosphoinositol pentakisphosphate or PP-IP5), and IP8 (bisdiphosphoinositol tetrakisphosphate or (PP)2-IP4). These energy-rich small molecules are present in all eukaryotic cells, from yeast to mammals, and are involved in a wide range of cellular functions including apoptosis, vesicle trafficking, DNA repair, osmoregulation, phosphate homeostasis, insulin sensitivity, immune signalling, cell cycle regulation, and ribosome synthesis. Identified more than 20 years ago, there is still only a rudimentary understanding of the mechanisms by which inositol pyrophosphates participate in these myriad pathways governing cell physiology and homeostasis. The unique stereochemical and bioenergetic properties these molecules possess as a consequence of the presence of one or two pyrophosphate moieties in the vicinity of densely packed monophosphates are likely to form the molecular basis for their participation in multiple signalling and metabolic pathways. The aim of this review is to provide first time researchers in this area with an introduction to inositol pyrophosphates and a comprehensive overview on their cellular functions.
Published: 4 July 2013
Journal: Amino Acids
Amino Acids, Volume 45, pp 751-754; https://doi.org/10.1007/s00726-013-1512-2

Abstract:
Proteins with polybasic clusters bind to negatively charged phosphoinositides at the cell membrane. In this review, I have briefly discussed the types of phosphoinositides naturally found on membrane surfaces and how they recruit protein complexes for carrying out the process of signal transduction. A large number of researchers from around the world are now focusing their attention on protein–membrane binding, as these interactions have started to offer us a much better insight into the process of cell signaling. The main areas discussed in this brief review article include the phosphoinositide binding specificities of proteins and the role of their lipid binding in signaling processes downstream of membrane recruitment.
, Adolfo Saiardi, Hideo Tsukamoto, Tadayuki Satoh, Yoshiko Itoh, Johbu Itoh, , Shunya Takizawa, Shigeharu Takagi
The international journal of biochemistry & cell biology, Volume 42, pp 2065-2071; https://doi.org/10.1016/j.biocel.2010.09.013

The publisher has not yet granted permission to display this abstract.
Anutosh Chakraborty, Michael A. Koldobskiy, , Micah Maxwell, James J. Potter, Krishna R. Juluri, David Maag, Seyun Kim, Alex S. Huang, Megan J. Dailey, et al.
Published: 10 December 2010
Journal: Cell
Cell, Volume 143, pp 897-910; https://doi.org/10.1016/j.cell.2010.11.032

The publisher has not yet granted permission to display this abstract.
Michael A. Koldobskiy, Anutosh Chakraborty, , Adele M. Snowman, Krishna R. Juluri, M. Scott Vandiver, Seyun Kim, Shira Heletz,
Proceedings of the National Academy of Sciences of the United States of America, Volume 107, pp 20947-20951; https://doi.org/10.1073/pnas.1015671107

Abstract:
Inositol pyrophosphates have been implicated in numerous biological processes. Inositol hexakisphosphate kinase-2 (IP6K2), which generates the inositol pyrophosphate, diphosphoinositol pentakisphosphate (IP7), influences apoptotic cell death. The tumor suppressor p53 responds to genotoxic stress by engaging a transcriptional program leading to cell-cycle arrest or apoptosis. We demonstrate that IP6K2 is required for p53-mediated apoptosis and modulates the outcome of the p53 response. Gene disruption of IP6K2 in colorectal cancer cells selectively impairs p53-mediated apoptosis, instead favoring cell-cycle arrest. IP6K2 acts by binding directly to p53 and decreasing expression of proarrest gene targets such as the cyclin-dependent kinase inhibitor p21.
, Christopher Illies, Per-Olof Berggren
Published: 23 March 2010
Abstract:
High performance liquid chromatography (HPLC) is an essential analytical tool in the study of the large number of inositol phosphate isomers. This chapter focuses on the separation of inositol polyphosphates from [3H]myo-inositol labeled tissues and cells. We review the different HPLC columns that have been used to separate inositol phosphates and their advantages and disadvantages. We describe important elements of sample preparation for effective separations and give examples of how changing factors, such as pH, can considerably improve the resolving ability of the HPLC chromatogram.
Karsten Sauer, , Hongying Lin, Mark Sandberg, Georg W. Mayr
Published: 1 November 2009
Current Protocols in Immunology, Volume 87, pp 11.1.1-11.1.46; https://doi.org/10.1002/0471142735.im1101s87

The publisher has not yet granted permission to display this abstract.
, Julia Torres, Himali Y. Godage, Andrew M. Riley, Sixto Domínguez, Barry V. L. Potter, ,
Journal of Biological Inorganic Chemistry, Volume 14, pp 1001-1013; https://doi.org/10.1007/s00775-009-0510-z

Abstract:
The inositol phosphates are ubiquitous metabolites in eukaryotes, of which the most abundant are inositol hexakisphosphate (InsP6) and inositol 1,3,4,5,6-pentakisphosphate [Ins(1,3,4,5,6)P5)]. These two compounds, poorly understood functionally, have complicated complexation and solid formation behaviours with multivalent cations. For InsP6, we have previously described this chemistry and its biological implications (Veiga et al. in J Inorg Biochem 100:1800, 2006; Torres et al. in J Inorg Biochem 99:828, 2005). We now cover similar ground for Ins(1,3,4,5,6)P5, describing its interactions in solution with Na+, K+, Mg2+, Ca2+, Cu2+, Fe2+ and Fe3+, and its solid-formation equilibria with Ca2+ and Mg2+. Ins(1,3,4,5,6)P5 forms soluble complexes of 1:1 stoichiometry with all multivalent cations studied. The affinity for Fe3+ is similar to that of InsP6 and inositol 1,2,3-trisphosphate, indicating that the 1,2,3-trisphosphate motif, which Ins(1,3,4,5,6)P5 lacks, is not absolutely necessary for high-affinity Fe3+ complexation by inositol phosphates, even if it is necessary for their prevention of the Fenton reaction. With excess Ca2+ and Mg2+, Ins(1,3,4,5,6)P5 also forms the polymetallic complexes [M4(H2L)] [where L is fully deprotonated Ins(1,3,4,5,6)P5]. However, unlike InsP6, Ins(1,3,4,5,6)P5 is predicted not to be fully associated with Mg2+ under simulated cytosolic/nuclear conditions. The neutral Mg2+ and Ca2+ complexes have significant windows of solubility, but they precipitate as [Mg4(H2L)]·23H2O or [Ca4(H2L)]·16H2O whenever they exceed 135 and 56 μM in concentration, respectively. Nonetheless, the low stability of the [M4(H2L)] complexes means that the 1:1 species contribute to the overall solubility of Ins(1,3,4,5,6)P5 even under significant Mg2+ or Ca2+ excesses. We summarize the solubility behaviour of Ins(1,3,4,5,6)P5 in straightforward plots.
Ling Yang, Jeff M. Reece, Jaiesoon Cho, Carl D. Bortner,
Published: 1 April 2008
Journal of Biological Chemistry, Volume 283, pp 11823-11831; https://doi.org/10.1074/jbc.m800308200

The publisher has not yet granted permission to display this abstract.
Petra Draškovič, Adolfo Saiardi, , Adam Burton, Gregor Ilc, Miroslav Kovačevič, Solomon H. Snyder,
Published: 21 March 2008
Cell Chemical Biology, Volume 15, pp 274-286; https://doi.org/10.1016/j.chembiol.2008.01.011

The publisher has not yet granted permission to display this abstract.
Jae H. Choi, Jason Williams, Jaiesoon Cho, ,
Published: 1 October 2007
Journal of Biological Chemistry, Volume 282, pp 30763-30775; https://doi.org/10.1074/jbc.m704655200

Abstract:
Mammalian cells utilize multiple signaling mechanisms to protect against the osmotic stress that accompanies plasma membrane ion transport, solute uptake, and turnover of protein and carbohydrates (Schliess, F., and Haussinger, D. (2002) Biol. Chem. 383, 577–583). Recently, osmotic stress was found to increase synthesis of bisdiphosphoinositol tetrakisphosphate ((PP)2-InsP4), a high energy inositol pyrophosphate (Pesesse, X., Choi, K., Zhang, T., and Shears, S. B. (2004) J. Biol. Chem. 279, 43378–43381). Here, we describe the purification from rat brain of a diphosphoinositol pentakisphosphate kinase (PPIP5K) that synthesizes (PP)2-InsP4. Partial amino acid sequence, obtained by mass spectrometry, matched the sequence of a 160-kDa rat protein containing a putative ATP-grasp kinase domain. BLAST searches uncovered two human isoforms (PPIP5K1 (160 kDa) and PPIP5K2 (138 kDa)). Recombinant human PPIP5K1, expressed in Escherichia coli, was found to phosphorylate diphosphoinositol pentakisphosphate (PP-InsP5) to (PP)2-InsP4 (Vmax = 8.3 nmol/mg of protein/min; Km = 0.34 μm). Overexpression in human embryonic kidney cells of either PPIP5K1 or PPIP5K2 substantially increased levels of (PP)2-InsP4, whereas overexpression of a catalytically dead PPIP5K1D332A mutant had no effect. PPIP5K1 and PPIP5K2 were more active against PP-InsP5 than InsP6, both in vitro and in vivo. Analysis by confocal immunofluorescence showed PPIP5K1 to be distributed throughout the cytoplasm but excluded from the nucleus. Immunopurification of overexpressed PPIP5K1 from osmotically stressed HEK cells (0.2 m sorbitol; 30 min) revealed a persistent, 3.9 ± 0.4-fold activation when compared with control cells. PPIP5Ks are likely to be important signaling enzymes.
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