Do mammals make all their own inositol hexakisphosphate?

Letcher, Andrew J.; Schell, Michael J.; Irvine, Robin F.

doi:10.1042/bj20081417

Cited by 91 publications

(94 citation statements)

References 57 publications

(88 reference statements)

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“…However, another species of yeast, Schizosaccharomyces pombe contains only 36 M InsP 6 (Ingram et al, 2003). All of the other published estimates of cellular InsP 6 levels-including some direct mass assaysare in the range of 15 to 60 M (Szwergold et al, 1987;Pittet et al, 1989;Irvine and Schell, 2001;Barker et al, 2004;Letcher et al, 2008). So 100 M InsP 6 , although not an implausible concentration, would certainly be an unusually high value, which means that the levels of PP-InsP 5 in S. cerevisiae may also have been overestimated.…”

Section: Do Cells Contain "Receptors" For Diphosphoinositol Polyphospmentioning

confidence: 99%

Diphosphoinositol Polyphosphates: Metabolic Messengers?

Shears¹

2009

Mol Pharmacol

138

148

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The diphosphoinositol polyphosphates ("inositol pyrophosphates") are a specialized subgroup of the inositol phosphate signaling family. This review proposes that many of the current data concerning the metabolic turnover and biological effects of the diphosphoinositol polyphosphates are linked by a common theme: these polyphosphates act as metabolic messengers. This review will also discuss the latest proposals concerning possible molecular mechanisms of action of this intriguing class of molecules.The discovery of cyclic AMP Sutherland and Rall, 1958) introduced us to the concept of a "second messenger" (Robison et al., 1968): a diffusible molecule (or ion) that, in response to an extracellular stimulus, is rapidly generated at (or released from) a particular subcellular site and then regulates particular effector proteins within the cell so as to elicit a cellular response. Of course, evolution has a remarkable tendency to repeat a good idea, so many different second messengers are now known. The inositol phosphate family represents the convergence of several "good signaling ideas," most notably in their use of a recurring theme in the cell-signaling genre: phosphate groups. Phosphates have two especially prominent features that facilitate specificity of interactions between cell signaling entities. First, the bulky nature of the phosphate group imposes geometric constraints on ligand-protein and protein-protein interactions. Second, the phosphate's negative charge at physiological pH bestows specificity on its interactions with target proteins through multiple ionic and hydrogen bonds. The negative charges on the phosphate group also make soluble, phosphorylated molecules lipid-impermeant, so that they can be retained inside cells.Inositol offers several additional assets for a signaling molecule. It is chemically stable, it is small (hence it diffuses through cytosol quickly), and it is only a short synthetic offshoot from the glycolytic pathway (Sherman et al., 1977). There is also a functionally significant plane of symmetry across the 2/5-axis of the inositol ring (Fig. 1). That symmetry permits one inositol phosphate to imitate another's threedimensional phosphate recognition pattern when the orientation of the inositol ring changes in relation to the protein's ligand-binding site (Wilcox et al., 1994), although in addition the binding site itself has to be somewhat flexible . This phenomenon provides a molecular explanation for the metabolic promiscuity of certain inositol phosphate kinases (for review, see Shears, 2004), and it also facilitates functionally important metabolic interactions between differ-

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Section: Do Cells Contain "Receptors" For Diphosphoinositol Polyphospmentioning

confidence: 99%

Diphosphoinositol Polyphosphates: Metabolic Messengers?

Shears¹

2009

Mol Pharmacol

138

148

View full text Add to dashboard Cite

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“…The InsP 6 stands out because it is a naturally occurring compound, which may explain its low cytotoxicity in relation to normal cells, even when it is in the form of a metal complex with Ni(II). InsP 6 is a substance that is common to organisms; it is present in the cells of all mammals, which absorb it from food (Letcher et al, 2008;Vucenik et al, 2005;Grases et al, 2001a,b). Contrary to what was believed some time ago, InsP 6 is not only synthesized by plants; it has been proven that it is synthesized by mammalian cells (Letcher et al, 2008).…”

Section: Discussionmentioning

confidence: 97%

“…InsP 6 is a substance that is common to organisms; it is present in the cells of all mammals, which absorb it from food (Letcher et al, 2008;Vucenik et al, 2005;Grases et al, 2001a,b). Contrary to what was believed some time ago, InsP 6 is not only synthesized by plants; it has been proven that it is synthesized by mammalian cells (Letcher et al, 2008). According to Vucenik et al (2005), the physiological concentration of InsP 6 in humans can reach up to 100 μM.…”

Section: Discussionmentioning

confidence: 97%

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Cytotoxic effect of inositol hexaphosphate and its Ni(II) complex on human acute leukemia Jurkat T cells

Lima

Kanunfre

Andrade

et al. 2015

Toxicology in Vitro

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Inositol hexaphosphate (InsP6) is present in cereals, legumes, nuts and seed oils and is biologically active against some tumor and cancer cells. Herein, this study aimed at evaluating the cellular toxicity, antiproliferative activity and effects on cell cycle progression of free InsP6 and InsP6-Ni(II) of leukemic T (Jurkat) and normal human cells. Treatments with InsP6 at concentrations between 1.0 and 4.0mM significantly decreased the viability of Jurkat cells, but showed no cytotoxic effect on normal human lymphocytes. Treatment with InsP6-Ni(II) complex at concentrations between 0.05 and 0.30 mM showed an anti-proliferative dose and a time-dependent effect, with significantly reduced cell viability of Jurkat cells but showed no cytotoxic effect on normal human lymphocytes as compared to the control. Ni(II) free ion was toxic to normal cells while InsP6-Ni(II) had no cytotoxic effect. The InsP6-Ni(II) complex potentiated (up to 10×) the antiproliferative effect of free InsP6 on Jurkat cells. The cytometric flow assay showed that InsP6 led to an accumulation of cells in the G0/G1 phase of the cell cycle, accompanied by a decrease in the number of cells in S and G2/M phases, whereas InsP6-Ni(II) has led to an accumulation of cells in the S and G2/M phases. Our findings showed that InsP6-Ni(II) potentiates cytotoxic effects of InsP6 on Jurkat cells and may be a potential adjuvant in the treatment of cancer.

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“…IP 6 is one of the most abundant IPs in eukaryotes, with intracellular concentration approaching 10 -50 µM in human cells (4)(5)(6)(7)(8). IP 6 metabolism in yeast and metazoans involves complex networks of IP kinases and phosphatases maintaining a high steady-state concentration of IP 6 , which is in rapid flux and responsive to changes in kinase or phosphatase activity (9)(10)(11)(12)(13)(14).…”

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confidence: 99%

Synthesis of Biotinylated Inositol Hexakisphosphate To Study DNA Double-Strand Break Repair and Affinity Capture of IP₆-Binding Proteins

2015

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Inositol hexakisphosphate (IP6) is a soluble inositol polyphosphate, which is abundant in mammalian cells. Despite the participation of IP6 in critical cellular functions, few IP6-binding proteins have been characterized. We report on the synthesis, characterization, and application of biotin-labeled IP6 (IP6-biotin), which has biotin attached at position 2 of the myo-inositol ring via an aminohexyl linker. Like natural IP6, IP6-biotin stimulated DNA ligation by nonhomologous end joining (NHEJ) in vitro. The Ku protein is a required NHEJ factor that has been shown to bind IP6. We found that IP6-biotin could affinity capture Ku and other required NHEJ factors from human cell extracts, including the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), XRCC4, and XLF. Direct binding studies with recombinant proteins show that Ku is the only NHEJ factor with affinity for IP6-biotin. DNA-PKcs, XLF, and the XRCC4:ligase IV complex interact with Ku in cell extracts and likely interact indirectly with IP6-biotin. IP6-biotin was used to tether streptavidin to Ku, which inhibited NHEJ in vitro. These proof-of-concept experiments suggest that molecules like IP6-biotin might be used to molecularly target biologically important proteins that bind IP6. IP6-biotin affinity capture experiments show that numerous proteins specifically bind IP6-biotin, including casein kinase 2, which is known to bind IP6, and nucleolin. Protein binding to IP6-biotin is selective, as IP3, IP4, and IP5 did not compete for binding of proteins to IP6-biotin. Our results document IP6-biotin as a useful tool for investigating the role of IP6 in biological systems.

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Do mammals make all their own inositol hexakisphosphate?

Cited by 91 publications

References 57 publications

Diphosphoinositol Polyphosphates: Metabolic Messengers?

Diphosphoinositol Polyphosphates: Metabolic Messengers?

Cytotoxic effect of inositol hexaphosphate and its Ni(II) complex on human acute leukemia Jurkat T cells

Synthesis of Biotinylated Inositol Hexakisphosphate To Study DNA Double-Strand Break Repair and Affinity Capture of IP₆-Binding Proteins

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Do mammals make all their own inositol hexakisphosphate?

Cited by 91 publications

References 57 publications

Diphosphoinositol Polyphosphates: Metabolic Messengers?

Diphosphoinositol Polyphosphates: Metabolic Messengers?

Cytotoxic effect of inositol hexaphosphate and its Ni(II) complex on human acute leukemia Jurkat T cells

Synthesis of Biotinylated Inositol Hexakisphosphate To Study DNA Double-Strand Break Repair and Affinity Capture of IP6-Binding Proteins

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Synthesis of Biotinylated Inositol Hexakisphosphate To Study DNA Double-Strand Break Repair and Affinity Capture of IP₆-Binding Proteins