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Annual Review of Biochemistry

Volume 93, 2024

Inositol Pyrophosphates as Versatile Metabolic Messengers

Abstract

Discovered in 1993, inositol pyrophosphates are evolutionarily conserved signaling metabolites whose versatile modes of action are being increasingly appreciated. These include their emerging roles as energy regulators, phosphodonors, steric/allosteric regulators, and G protein–coupled receptor messengers. Through studying enzymes that metabolize inositol pyrophosphates, progress has also been made in elucidating the various cellular and physiological functions of these pyrophosphate-containing, energetic molecules. The two main forms of inositol pyrophosphates, 5-IP and IP, synthesized respectively by inositol-hexakisphosphate kinases (IP6Ks) and diphosphoinositol pentakisphosphate kinases (PPIP5Ks), regulate phosphate homeostasis, ATP synthesis, and several other metabolic processes ranging from insulin secretion to cellular energy utilization. Here, we review the current understanding of the catalytic and regulatory mechanisms of IP6Ks and PPIP5Ks, as well as their counteracting phosphatases. We also highlight the genetic and cellular evidence implicating inositol pyrophosphates as essential mediators of mammalian metabolic homeostasis.

Keyword(s): energy metabolism, inositol hexakisphosphate kinase, inositol pyrophosphates, IP6K, phosphate homeostasis, PPIP5K
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/content/journals/10.1146/annurev-biochem-030222-121901
2024-08-02
2025-04-21
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Literature Cited

  1. 1.
    Thomas MP, Mills SJ, Potter BVL. 2016.. The “other” inositols and their phosphates: synthesis, biology, and medicine (with recent advances in myo-inositol chemistry). . Angew. Chem. Int. Ed. Engl. 55::1614–50
     [Crossref] [Google Scholar]
  2. 2.
    Al-Suoda H, Ligor M, Ratiu I-A, Rafinska K, Góreckid R, Buszewskia B. 2017.. A window on cyclitols: characterization and analytics of inositols. . Phytochem. Lett. 20::507–19
     [Crossref] [Google Scholar]
  3. 3.
    Barker CJ, Illies C, Gaboardi GC, Berggren P-O. 2009.. Inositol pyrophosphates: structure, enzymology and function. . Cell Mol. Life Sci. 66::3851–71
     [Crossref] [Google Scholar]
  4. 4.
    Wundenberg T, Grabinski N, Lin H, Mayr GW. 2014.. Discovery of InsP6-kinases as InsP6-dephosphorylating enzymes provides a new mechanism of cytosolic InsP6 degradation driven by the cellular ATP/ADP ratio. . Biochem. J. 462::173–84
     [Crossref] [Google Scholar]
  5. 5.
    Irvine RF, Schell MJ. 2001.. Back in the water: the return of the inositol phosphates. . Nat. Rev. Mol. Cell Biol. 2::327–38
     [Crossref] [Google Scholar]
  6. 6.
    Irvine RF. 2003.. 20 years of Ins(1,4,5)P3, and 40 years before. . Nat. Rev. Mol. Cell Biol. 4::586–90
     [Crossref] [Google Scholar]
  7. 7.
    Shears SB. 2004.. How versatile are inositol phosphate kinases?. Biochem. J. 377::265–80
     [Crossref] [Google Scholar]
  8. 8.
    Laha D, Portela-Torres P, Desfougeres Y, Saiardi A. 2021.. Inositol phosphate kinases in the eukaryote landscape. . Adv. Biol. Regul. 79::100782
     [Crossref] [Google Scholar]
  9. 9.
    Berridge MJ, Lipp P, Bootman MD. 2000.. The versatility and universality of calcium signalling. . Nat. Rev. Mol. Cell Biol. 1::11–21
     [Crossref] [Google Scholar]
  10. 10.
    Dewaste V, Pouillon V, Moreau C, Shears S, Takazawa K, Erneux C. 2000.. Cloning and expression of a cDNA encoding human inositol 1,4,5-trisphosphate 3-kinase C. . Biochem. J. 352::343–51
     [Crossref] [Google Scholar]
  11. 11.
    Takazawa K, Lemos M, Delvaux A, Lejeune C, Dumont JE, Erneux C. 1990.. Rat brain inositol 1,4,5-trisphosphate 3-kinase. Ca2+-sensitivity, purification and antibody production. . Biochem. J. 268::213–17
     [Crossref] [Google Scholar]
  12. 12.
    Saiardi A, Erdjument-Bromage H, Snowman AM, Tempst P, Snyder SH. 1999.. Synthesis of diphosphoinositol pentakisphosphate by a newly identified family of higher inositol polyphosphate kinases. . Curr. Biol. 9::1323–26
     [Crossref] [Google Scholar]
  13. 13.
    Verbsky JW, Wilson MP, Kisseleva MV, Majerus PW, Wente SR. 2002.. The synthesis of inositol hexakisphosphate: characterization of human inositol 1,3,4,5,6-pentakisphosphate 2-kinase. . J. Biol. Chem. 277::31857–62
     [Crossref] [Google Scholar]
  14. 14.
    Desfougeres Y, Wilson MSC, Laha D, Miller GJ, Saiardi A. 2019.. ITPK1 mediates the lipid-independent synthesis of inositol phosphates controlled by metabolism. . PNAS 116::24551–61
     [Crossref] [Google Scholar]
  15. 15.
    Mayr GW, Radenberg T, Thiel U, Vogel G, Stephens LR. 1992.. Phosphoinositol diphosphates: non-enzymic formation in vitro and occurrence in vivo in the cellular slime mold Dictyostelium. . Carbohydr. Res. 234::247–62
     [Crossref] [Google Scholar]
  16. 16.
    Menniti F, Miller R, Putney J Jr., Shears SB. 1993.. Turnover of inositol polyphosphate pyrophosphates in pancreatoma cells. . J. Biol. Chem. 268::3850–56
     [Crossref] [Google Scholar]
  17. 17.
    Saiardi AJ. 2012.. How inositol pyrophosphates control cellular phosphate homeostasis?. Adv. Biol. Regul. 52::351–59
     [Crossref] [Google Scholar]
  18. 18.
    Shears SB. Understanding the biological significance of diphosphoinositol polyphosphates (‘inositol pyrophosphates’). . Biochem. Soc. Symp. 74::211–21
     [Google Scholar]
  19. 19.
    Chakraborty A, Kim S, Snyder SH. 2011.. Inositol pyrophosphates as mammalian cell signals. . Sci. Signal. 4::re1
     [Crossref] [Google Scholar]
  20. 20.
    Koldobskiy MA, Snyder SH. 2011.. Inositol pyrophosphates in cell death and life. . Cell Cycle 10::568–70
     [Crossref] [Google Scholar]
  21. 21.
    Qiu D, Gu C, Liu G, Ritter K, Eisenbeis VB, et al. 2023.. Capillary electrophoresis mass spectrometry identifies new isomers of inositol pyrophosphates in mammalian tissues. . Chem. Sci. 14::658–67
     [Crossref] [Google Scholar]
  22. 22.
    Shears SB. 2015.. Inositol pyrophosphates: why so many phosphates?. Adv. Biol. Regul. 57::203–16
     [Crossref] [Google Scholar]
  23. 23.
    Nguyen Trung M, Furkert D, Fiedler D. 2022.. Versatile signaling mechanisms of inositol pyrophosphates. . Curr. Opin. Chem. Biol. 70::102177
     [Crossref] [Google Scholar]
  24. 24.
    Ganguli S, Shah A, Hamid A, Singh A, Palakurti R, Bhandari R. 2020.. A high energy phosphate jump—from pyrophospho-inositol to pyrophospho-serine. . Adv. Biol. Regul. 75::100662
     [Crossref] [Google Scholar]
  25. 25.
    Saiardi A, Bhandari R, Resnick AC, Snowman AM, Snyder SH. 2004.. Phosphorylation of proteins by inositol pyrophosphates. . Science 306::2101–5
     [Crossref] [Google Scholar]
  26. 26.
    Bhandari R, Saiardi A, Ahmadibeni Y, Snowman AM, Resnick AC, et al. 2007.. Protein pyrophosphorylation by inositol pyrophosphates is a posttranslational event. . PNAS 104::15305–10
     [Crossref] [Google Scholar]
  27. 27.
    Lin H, Fridy PC, Ribeiro AA, Choi JH, Barma DK, et al. 2009.. Structural analysis and detection of biological inositol pyrophosphates reveal that the family of VIP/diphosphoinositol pentakisphosphate kinases are 1/3-kinases. . J. Biol. Chem. 284::1863–72
     [Crossref] [Google Scholar]
  28. 28.
    Wundenberg T, Mayr GW. 2012.. Synthesis and biological actions of diphosphoinositol phosphates (inositol pyrophosphates), regulators of cell homeostasis. . Biol. Chem. 393::979–98
     [Crossref] [Google Scholar]
  29. 29.
    Albert C, Safrany ST, Bembenek ME, Reddy KM, Reddy K, et al. 1997.. Biological variability in the structures of diphosphoinositol polyphosphates in Dictyostelium discoideum and mammalian cells. . Biochem. J. 327::553–60
     [Crossref] [Google Scholar]
  30. 30.
    Barker CJ, Wright J, Hughes PJ, Kirk CJ, Michell RH. 2004.. Complex changes in cellular inositol phosphate complement accompany transit through the cell cycle. . Biochem. J. 380::465–73
     [Crossref] [Google Scholar]
  31. 31.
    Illies C, Gromada J, Fiume R, Leibiger B, Yu J, et al. 2007.. Requirement of inositol pyrophosphates for full exocytotic capacity in pancreatic β cells. . Science 318::1299–302
     [Crossref] [Google Scholar]
  32. 32.
    Kilari RS, Weaver JD, Shears SB, Safrany ST. 2013.. Understanding inositol pyrophosphate metabolism and function: kinetic characterization of the DIPPs. . FEBS Lett. 587::3464–70
     [Crossref] [Google Scholar]
  33. 33.
    Choi K, Mollapour E, Shears SB. 2005.. Signal transduction during environmental stress: InsP8 operates within highly restricted contexts. . Cell Signal. 17::1533–41
     [Crossref] [Google Scholar]
  34. 34.
    Choi K, Mollapour E, Choi JH, Shears SB. 2008.. Cellular energetic status supervises the synthesis of bis-diphosphoinositol tetrakisphosphate independently of AMP-activated protein kinase. . Mol. Pharmacol. 74::527–36
     [Crossref] [Google Scholar]
  35. 35.
    Shears SB, Weaver JD, Wang HJ. 2013.. Structural insight into inositol pyrophosphate turnover. . Adv. Biol. Regul. 53::19–27
     [Crossref] [Google Scholar]
  36. 36.
    Wilson MS, Bulley SJ, Pisani F, Irvine RF, Saiardi A. 2015.. A novel method for the purification of inositol phosphates from biological samples reveals that no phytate is present in human plasma or urine. . Open Biol. 5::150014
     [Crossref] [Google Scholar]
  37. 37.
    Glennon MC, Shears SB. 1993.. Turnover of inositol pentakisphosphates, inositol hexakisphosphate and diphosphoinositol polyphosphates in primary cultured hepatocytes. . Biochem. J. 293::583–90
     [Crossref] [Google Scholar]
  38. 38.
    Draškovič P, Saiardi A, Bhandari R, Burton A, Ilc G, et al. 2008.. Inositol hexakisphosphate kinase products contain diphosphate and triphosphate groups. . Chem. Biol. 15::274–86
     [Crossref] [Google Scholar]
  39. 39.
    Voglmaier SM, Bembenek ME, Kaplin AI, Dormán G, Olszewski JD, et al. 1996.. Purified inositol hexakisphosphate kinase is an ATP synthase: diphosphoinositol pentakisphosphate as a high-energy phosphate donor. . PNAS 93::4305–10
     [Crossref] [Google Scholar]
  40. 40.
    Saiardi A, Nagata E, Luo HR, Snowman AM, Snyder SH. 2001.. Identification and characterization of a novel inositol hexakisphosphate kinase. . J. Biol. Chem. 276::39179–85
     [Crossref] [Google Scholar]
  41. 41.
    Thomas MP, Potter BV. 2014.. The enzymes of human diphosphoinositol polyphosphate metabolism. . FEBS J. 281::14–33
     [Crossref] [Google Scholar]
  42. 42.
    Norbis F, Boll M, Stange G, Markovich D, Verrey F, et al. 1997.. Identification of a cDNA/protein leading to an increased Pi-uptake in Xenopus laevis oocytes. . J. Membr. Biol. 156::19–24
     [Crossref] [Google Scholar]
  43. 43.
    Schell MJ, Letcher AJ, Brearley CA, Biber J, Murer H, Irvine RF. 1999.. PiUS (Pi uptake stimulator) is an inositol hexakisphosphate kinase. . FEBS Lett. 461::169–72
     [Crossref] [Google Scholar]
  44. 44.
    Wang H, DeRose EF, London RE, Shears SB. 2014.. IP6K structure and the molecular determinants of catalytic specificity in an inositol phosphate kinase family. . Nat. Commun. 5::4178
     [Crossref] [Google Scholar]
  45. 45.
    Shears SB, Wang H. 2019.. Inositol phosphate kinases: expanding the biological significance of the universal core of the protein kinase fold. . Adv. Biol. Regul. 71::118–27
     [Crossref] [Google Scholar]
  46. 46.
    Voglmaier SM, Bembenek ME, Kaplin AI, Dormán G, Olszewski JD, et al. 1996.. Purified inositol hexakisphosphate kinase is an ATP synthase: diphosphoinositol pentakisphosphate as a high-energy phosphate donor. . PNAS 93::4305–10
     [Crossref] [Google Scholar]
  47. 47.
    Rajasekaran SS, Kim J, Gaboardi GC, Gromada J, Shears SB, et al. 2018.. Inositol hexakisphosphate kinase 1 is a metabolic sensor in pancreatic β-cells. . Cell Signal. 46::120–28
     [Crossref] [Google Scholar]
  48. 48.
    Choi JH, Williams J, Cho J, Falck J, Shears SB. 2007.. Purification, sequencing, and molecular identification of a mammalian PP-InsP5 kinase that is activated when cells are exposed to hyperosmotic stress. . J. Biol. Chem. 282::30763–75
     [Crossref] [Google Scholar]
  49. 49.
    Fridy PC, Otto JC, Dollins DE, York JD. 2007.. Cloning and characterization of two human VIP1-like inositol hexakisphosphate and diphosphoinositol pentakisphosphate kinases. . J. Biol. Chem. 282::30754–62
     [Crossref] [Google Scholar]
  50. 50.
    Shears SB, Baughman BM, Gu C, Nair VS, Wang H. 2017.. The significance of the 1-kinase/1-phosphatase activities of the PPIP5K family. . Adv. Biol. Regul. 63::98–106
     [Crossref] [Google Scholar]
  51. 51.
    Mulugu S, Bai W, Fridy PC, Bastidas RJ, Otto JC, et al. 2007.. A conserved family of enzymes that phosphorylate inositol hexakisphosphate. . Science 316::106–9
     [Crossref] [Google Scholar]
  52. 52.
    Wang H, Falck J, Hall TMT, Shears SB. 2012.. Structural basis for an inositol pyrophosphate kinase surmounting phosphate crowding. . Nat. Chem. Biol. 8::111–16
     [Crossref] [Google Scholar]
  53. 53.
    Dollins DE, Bai W, Fridy PC, Otto JC, Neubauer JL, et al. 2020.. Vip1 is a kinase and pyrophosphatase switch that regulates inositol diphosphate signaling. . PNAS 117::9356–64
     [Crossref] [Google Scholar]
  54. 54.
    Gu C, Nguyen H-N, Hofer A, Jessen HJ, Dai X, et al. 2017.. The significance of the bifunctional kinase/phosphatase activities of diphosphoinositol pentakisphosphate kinases (PPIP5Ks) for coupling inositol pyrophosphate cell signaling to cellular phosphate homeostasis. . J. Biol. Chem. 292::4544–55
     [Crossref] [Google Scholar]
  55. 55.
    Randall TA, Gu C, Li X, Wang H, Shears SB. 2020.. A two-way switch for inositol pyrophosphate signaling: evolutionary history and biological significance of a unique, bifunctional kinase/phosphatase. . Adv. Biol. Regul. 75::100674
     [Crossref] [Google Scholar]
  56. 56.
    Safrany ST, Caffrey JJ, Yang X, Bembenek ME, Moyer MB, et al. 1998.. A novel context for the ‘MutT’ module, a guardian of cell integrity, in a diphosphoinositol polyphosphate phosphohydrolase. . EMBO J. 17::6599–607
     [Crossref] [Google Scholar]
  57. 57.
    Caffrey JJ, Safrany ST, Yang X, Shears SB. 2000.. Discovery of molecular and catalytic diversity among human diphosphoinositol-polyphosphate phosphohydrolases: an expanding NUDT family. . J. Biol. Chem. 275::12730–36
     [Crossref] [Google Scholar]
  58. 58.
    Zong G, Jork N, Hostachy S, Fiedler D, Jessen HJ, et al. 2021.. New structural insights reveal an expanded reaction cycle for inositol pyrophosphate hydrolysis by human DIPP1. . FASEB J. 35::e21275
     [Crossref] [Google Scholar]
  59. 59.
    Steidle EA, Chong LS, Wu M, Crooke E, Fiedler D, et al. 2016.. A novel inositol pyrophosphate phosphatase in Saccharomyces cerevisiae: Siw14 protein selectively cleaves the β-phosphate from 5-diphosphoinositol pentakisphosphate (5PP-IP5). . J. Biol. Chem. 291::6772–83
     [Crossref] [Google Scholar]
  60. 60.
    York SJ, Armbruster BN, Greenwell P, Petes TD, York JD. 2005.. Inositol diphosphate signaling regulates telomere length. . J. Biol. Chem. 280::4264–69
     [Crossref] [Google Scholar]
  61. 61.
    Ingram SW, Safrany ST, Barnes LD. 2003.. Disruption and overexpression of the Schizosaccharomyces pombeaps1 gene, and effects on growth rate, morphology and intracellular diadenosine 5′,5-P1,P5-pentaphosphate and diphosphoinositol polyphosphate concentrations. . Biochem. J. 369::519–28
     [Crossref] [Google Scholar]
  62. 62.
    Sahu S, Gordon J, Gu C, Sobhany M, Fiedler D, et al. 2023.. Nucleolar architecture is modulated by a small molecule, the inositol pyrophosphate 5-InsP7. . Biomolecules 13::153
     [Crossref] [Google Scholar]
  63. 63.
    Rao F, Xu J, Khan AB, Gadalla MM, Cha JY, et al. 2014.. Inositol hexakisphosphate kinase-1 mediates assembly/disassembly of the CRL4-signalosome complex to regulate DNA repair and cell death. . PNAS 111::16005–10
     [Crossref] [Google Scholar]
  64. 64.
    Nagata E, Luo HR, Saiardi A, Bae BII, Suzuki N, Snyder SH. 2005.. Inositol hexakisphosphate kinase-2, a physiologic mediator of cell death. . J. Biol. Chem. 280::1634–40
     [Crossref] [Google Scholar]
  65. 65.
    Zhang X, Li N, Zhang J, Zhang Y, Yang X, et al. 2021.. 5-IP7 is a GPCR messenger mediating neural control of synaptotagmin-dependent insulin exocytosis and glucose homeostasis. . Nat. Metab. 3::1400–14
     [Crossref] [Google Scholar]
  66. 66.
    Chakraborty A, Koldobskiy MA, Bello NT, Maxwell M, Potter JJ, et al. 2010.. Inositol pyrophosphates inhibit Akt signaling, thereby regulating insulin sensitivity and weight gain. . Cell 143::897–910
     [Crossref] [Google Scholar]
  67. 67.
    Gu C, Nguyen H-N, Ganini D, Chen Z, Jessen HJ, et al. 2017.. KO of 5-InsP7 kinase activity transforms the HCT116 colon cancer cell line into a hypermetabolic, growth-inhibited phenotype. . PNAS 114::11968–73
     [Crossref] [Google Scholar]
  68. 68.
    Pesesse X, Choi K, Zhang T, Shears SB. 2004.. Signaling by higher inositol polyphosphates: Synthesis of bisdiphosphoinositol tetrakisphosphate (“InsP8”) is selectively activated by hyperosmotic stress. . J. Biol. Chem. 279::43378–81
     [Crossref] [Google Scholar]
  69. 69.
    Nagpal L, Fu C, Snyder SH. 2018.. Inositol hexakisphosphate kinase-2 in cerebellar granule cells regulates Purkinje cells and motor coordination via protein 4.1 N. . J. Neurosci. 38::7409–19
     [Crossref] [Google Scholar]
  70. 70.
    Moritoh Y, Oka M, Yasuhara Y, Hozumi H, Iwachidow K, et al. 2016.. Inositol hexakisphosphate kinase 3 regulates metabolism and lifespan in mice. . Sci. Rep. 6::32072
     [Crossref] [Google Scholar]
  71. 71.
    Zhu Q, Ghoshal S, Rodrigues A, Gao S, Asterian A, et al. 2016.. Adipocyte-specific deletion of Ip6k1 reduces diet-induced obesity by enhancing AMPK-mediated thermogenesis. . J. Clin. Investig. 126::4273–88
     [Crossref] [Google Scholar]
  72. 72.
    Naufahu J, Elliott B, Markiv A, Dunning-Foreman P, McGrady M, et al. 2018.. High-intensity exercise decreases IP6K1 muscle content and improves insulin sensitivity (SI2*) in glucose-intolerant individuals. . J. Clin. Endocrinol. Metab. 103::1479–90
     [Crossref] [Google Scholar]
  73. 73.
    Bizzarri M, Dinicola S, Cucina A. 2017.. Modulation of both insulin resistance and cancer growth by inositol. . Curr. Pharm. Des. 23::5200–10
     [Crossref] [Google Scholar]
  74. 74.
    Aoki M, Sobek V, Maslyar DJ, Hecht A, Vogt PK. 2002.. Oncogenic transformation by β-catenin: deletion analysis and characterization of selected target genes. . Oncogene 21::6983–91
     [Crossref] [Google Scholar]
  75. 75.
    Ghoshal S, Tyagi R, Zhu Q, Chakraborty A. 2016.. Inositol hexakisphosphate kinase-1 interacts with perilipin1 to modulate lipolysis. . Int. J. Biochem. Cell Biol. 78::149–55
     [Crossref] [Google Scholar]
  76. 76.
    Yu W, Ye C, Greenberg ML. 2016.. Inositol hexakisphosphate kinase 1 (IP6K1) regulates inositol synthesis in mammalian cells. . J. Biol. Chem. 291::10437–44
     [Crossref] [Google Scholar]
  77. 77.
    Chakraborty A, Werner JK Jr., Koldobskiy MA, Mustafa AK, Juluri KR, et al. 2011.. Casein kinase-2 mediates cell survival through phosphorylation and degradation of inositol hexakisphosphate kinase-2. . PNAS 108::2205–9
     [Crossref] [Google Scholar]
  78. 78.
    Nair VS, Gu C, Janoshazi AK, Jessen HJ, Wang H, Shears SB. 2018.. Inositol pyrophosphate synthesis by diphosphoinositol pentakisphosphate kinase-1 is regulated by phosphatidylinositol(4,5)bisphosphate. . Biosci. Rep. 38::BSR20171549
     [Crossref] [Google Scholar]
  79. 79.
    Yong ST, Nguyen H-N, Choi JH, Bortner CD, Williams J, et al. 2015.. Identification of a functional nuclear translocation sequence in hPPIP5K2. . BMC Cell Biol. 16::17
     [Crossref] [Google Scholar]
  80. 80.
    Chakraborty A. 2018.. The inositol pyrophosphate pathway in health and diseases. . Biol. Rev. Camb. Philos. Soc. 93::1203–27
     [Crossref] [Google Scholar]
  81. 81.
    Shears SB, Wang H. 2020.. Metabolism and functions of inositol pyrophosphates: insights gained from the application of synthetic analogues. . Molecules 25::4515
     [Crossref] [Google Scholar]
  82. 82.
    Krober T, Bartsch SM, Fiedler D. 2022.. Pharmacological tools to investigate inositol polyphosphate kinases—enzymes of increasing therapeutic relevance. . Adv. Biol. Regul. 83::100836
     [Crossref] [Google Scholar]
  83. 83.
    Bhandari R, Juluri KR, Resnick AC, Snyder SH. 2008.. Gene deletion of inositol hexakisphosphate kinase 1 reveals inositol pyrophosphate regulation of insulin secretion, growth, and spermiogenesis. . PNAS 105::2349–53
     [Crossref] [Google Scholar]
  84. 84.
    Padmanabhan U, Dollins DE, Fridy PC, York JD, Downes CP. 2009.. Characterization of a selective inhibitor of inositol hexakisphosphate kinases: use in defining biological roles and metabolic relationships of inositol pyrophosphates. . J. Biol. Chem. 284::10571–82
     [Crossref] [Google Scholar]
  85. 85.
    Lee TS, Lee J-Y, Kyung JW, Yang Y, Park SJ, et al. 2016.. Inositol pyrophosphates inhibit synaptotagmin-dependent exocytosis. . PNAS 113::8314–19
     [Crossref] [Google Scholar]
  86. 86.
    Park SJ, Park H, Kim M-G, Zhang S, Park SE, et al. 2020.. Inositol pyrophosphate metabolism regulates presynaptic vesicle cycling at central synapses. . iScience 23::101000
     [Crossref] [Google Scholar]
  87. 87.
    Qiu D, Wilson MS, Eisenbeis VB, Harmel RK, Riemer E, et al. 2020.. Analysis of inositol phosphate metabolism by capillary electrophoresis electrospray ionization mass spectrometry. . Nat. Commun. 11::6035
     [Crossref] [Google Scholar]
  88. 88.
    Ito M, Fujii N, Wittwer C, Sasaki A, Tanaka M, et al. 2018.. Hydrophilic interaction liquid chromatography–tandem mass spectrometry for the quantitative analysis of mammalian-derived inositol poly/pyrophosphates. . J. Chromatogr. A 1573::87–97
     [Crossref] [Google Scholar]
  89. 89.
    Pavlovic I, Thakor DT, Vargas JR, McKinlay CJ, Hauke S, et al. 2016.. Cellular delivery and photochemical release of a caged inositol-pyrophosphate induces PH-domain translocation in cellulo. . Nat. Commun. 7::10622
     [Crossref] [Google Scholar]
  90. 90.
    Ghoshal S, Zhu Q, Asteian A, Lin H, Xu H, et al. 2016.. TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine] ameliorates diet induced obesity and insulin resistance via inhibition of the IP6K1 pathway. . Mol. Metab. 5::903–17
     [Crossref] [Google Scholar]
  91. 91.
    Sun D, Li S, Wu H, Zhang M, Zhang X, et al. 2015.. Oncostatin M (OSM) protects against cardiac ischaemia/reperfusion injury in diabetic mice by regulating apoptosis, mitochondrial biogenesis and insulin sensitivity. . J. Cell Mol. Med. 19::1296–307
     [Crossref] [Google Scholar]
  92. 92.
    Ghoshal S, Mukherjee S, Chakraborty M, Msengi EN, Haubner J, Chakraborty A. 2022.. Whole body Ip6k1 deletion protects mice from age-induced weight gain, insulin resistance and metabolic dysfunction. . Int. J. Mol. Sci. 23:(4):2059
     [Crossref] [Google Scholar]
  93. 93.
    Furkert D, Hostachy S, Nadler-Holly M, Fiedler D. 2020.. Triplexed affinity reagents to sample the mammalian inositol pyrophosphate interactome. . Cell Chem. Biol. 27::1097–108.e4
     [Crossref] [Google Scholar]
  94. 94.
    Lin H, Zhang X, Liu L, Fu Q, Zang C, et al. 2020.. Basis for metabolite-dependent Cullin-RING ligase deneddylation by the COP9 signalosome. . PNAS 117::4117–24
     [Crossref] [Google Scholar]
  95. 95.
    Scherer PC, Ding Y, Liu Z, Xu J, Mao H, et al. 2016.. Inositol hexakisphosphate (IP6) generated by IP5K mediates cullin-COP9 signalosome interactions and CRL function. . PNAS 113::3503–8
     [Crossref] [Google Scholar]
  96. 96.
    Blind RD. 2020.. Structural analyses of inositol phosphate second messengers bound to signaling effector proteins. . Adv. Biol. Regul. 75::100667
     [Crossref] [Google Scholar]
  97. 97.
    Lonetti A, Szijgyarto Z, Bosch D, Loss O, Azevedo C, Saiardi A. 2011.. Identification of an evolutionarily conserved family of inorganic polyphosphate endopolyphosphatases. . J. Biol. Chem. 286::31966–74
     [Crossref] [Google Scholar]
  98. 98.
    Ghosh S, Shukla D, Suman K, Lakshmi BJ, Manorama R, et al. 2013.. Inositol hexakisphosphate kinase 1 maintains hemostasis in mice by regulating platelet polyphosphate levels. . Blood 122::1478–86
     [Crossref] [Google Scholar]
  99. 99.
    Wild R, Gerasimaite R, Jung J-Y, Truffault V, Pavlovic I, et al. 2016.. Control of eukaryotic phosphate homeostasis by inositol polyphosphate sensor domains. . Science 352::986–90
     [Crossref] [Google Scholar]
  100. 100.
    Ye C, Bandara WM, Greenberg ML. 2013.. Regulation of inositol metabolism is fine-tuned by inositol pyrophosphates in Saccharomyces cerevisiae. . J. Biol. Chem. 288::24898–908
     [Crossref] [Google Scholar]
  101. 101.
    Lazcano P, Schmidtke MW, Onu CJ, Greenberg ML. 2022.. Phosphatidic acid inhibits inositol synthesis by inducing nuclear translocation of kinase IP6K1 and repression of myo-inositol-3-P synthase. . J. Biol. Chem. 298::102363
     [Crossref] [Google Scholar]
  102. 102.
    Burton A, Azevedo C, Andreassi C, Riccio A, Saiardi A. 2013.. Inositol pyrophosphates regulate JMJD2C-dependent histone demethylation. . PNAS 110::18970–75
     [Crossref] [Google Scholar]
  103. 103.
    Szijgyarto Z, Garedew A, Azevedo C, Saiardi AJS. 2011.. Influence of inositol pyrophosphates on cellular energy dynamics. . Science 334::802–5
     [Crossref] [Google Scholar]
  104. 104.
    Morrison BH, Bauer JA, Kalvakolanu DV, Lindner DJ. 2001.. Inositol hexakisphosphate kinase 2 mediates growth suppressive and apoptotic effects of interferon-β in ovarian carcinoma cells. . J. Biol. Chem. 276::24965–70
     [Crossref] [Google Scholar]
  105. 105.
    Nagpal L, Kornberg MD, Albacarys LK, Snyder SH. 2021.. Inositol hexakisphosphate kinase-2 determines cellular energy dynamics by regulating creatine kinase-B. . PNAS 118::e2020695118
     [Crossref] [Google Scholar]
  106. 106.
    Nagpal L, Kornberg MD, Snyder SH. 2022.. Inositol hexakisphosphate kinase-2 non-catalytically regulates mitophagy by attenuating PINK1 signaling. . PNAS 119::e2121946119
     [Crossref] [Google Scholar]
  107. 107.
    Ito M, Fujii N, Kohara S, Hori S, Tanaka M, et al. 2023.. Inositol pyrophosphate profiling reveals regulatory roles of IP6K2-dependent enhanced IP7 metabolism in the enteric nervous system. . J. Biol. Chem. 299:(3):102928
     [Crossref] [Google Scholar]
  108. 108.
    Rao F, Cha J, Xu J, Xu R, Vandiver MS, et al. 2014.. Inositol pyrophosphates mediate the DNA-PK/ATM-p53 cell death pathway by regulating CK2 phosphorylation of Tti1/Tel2. . Mol. Cell 54::119–32
     [Crossref] [Google Scholar]
  109. 109.
    Morrison BH, Haney R, Lamarre E, Drazba J, Prestwich GD, Lindner DJ. 2009.. Gene deletion of inositol hexakisphosphate kinase 2 predisposes to aerodigestive tract carcinoma. . Oncogene 28::2383–92
     [Crossref] [Google Scholar]
  110. 110.
    Rao F, Xu J, Fu C, Cha JY, Gadalla MM, et al. 2015.. Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1. . PNAS 112::1773–78
     [Crossref] [Google Scholar]
  111. 111.
    Jadav RS, Kumar D, Buwa N, Ganguli S, Thampatty SR, et al. 2016.. Deletion of inositol hexakisphosphate kinase 1 (IP6K1) reduces cell migration and invasion, conferring protection from aerodigestive tract carcinoma in mice. . Cell Signal. 28::1124–36
     [Crossref] [Google Scholar]
  112. 112.
    Fu C, Xu J, Cheng W, Rojas T, Chin AC, et al. 2017.. Neuronal migration is mediated by inositol hexakisphosphate kinase 1 via α-actinin and focal adhesion kinase. . PNAS 114::2036–41
     [Crossref] [Google Scholar]
  113. 113.
    Qi J, Cheng W, Gao Z, Chen Y, Shipton ML, et al. 2023.. Itraconazole inhibits endothelial cell migration by disrupting inositol pyrophosphate-dependent focal adhesion dynamics and cytoskeletal remodeling. . Biomed. Pharmacother. 161::114449
     [Crossref] [Google Scholar]
  114. 114.
    Wilson MS, Jessen HJ, Saiardi A. 2019.. The inositol hexakisphosphate kinases IP6K1 and -2 regulate human cellular phosphate homeostasis, including XPR1-mediated phosphate export. . J. Biol. Chem. 294::11597–608
     [Crossref] [Google Scholar]
  115. 115.
    Li X, Gu C, Hostachy S, Sahu S, Wittwer C, et al. 2020.. Control of XPR1-dependent cellular phosphate efflux by InsP8 is an exemplar for functionally-exclusive inositol pyrophosphate signaling. . PNAS 117::3568–74
     [Crossref] [Google Scholar]
  116. 116.
    Moritoh Y, Abe S-I, Akiyama H, Kobayashi A, Koyama R, et al. 2021.. The enzymatic activity of inositol hexakisphosphate kinase controls circulating phosphate in mammals. . Nat. Commun. 12::4847
     [Crossref] [Google Scholar]
  117. 117.
    Kestenbaum B, Glazer NL, Köttgen A, Felix JF, Hwang S-J, et al. 2010.. Common genetic variants associate with serum phosphorus concentration. . J. Am. Soc. Nephrol. 21::1223–32
     [Crossref] [Google Scholar]
  118. 118.
    Yousaf R, Gu C, Ahmed ZM, Khan SN, Friedman TB, et al. 2018.. Mutations in diphosphoinositol-pentakisphosphate kinase PPIP5K2 are associated with hearing loss in human and mouse. . PLOS Genet. 14::e1007297
     [Crossref] [Google Scholar]
  119. 119.
    Gu C, Liu J, Liu X, Zhang H, Luo J, et al. 2021.. Metabolic supervision by PPIP5K, an inositol pyrophosphate kinase/phosphatase, controls proliferation of the HCT116 tumor cell line. . PNAS 118::e2020187118
     [Crossref] [Google Scholar]
  120. 120.
    Dong J, Ma G, Sui L, Wei M, Satheesh V, et al. 2019.. Inositol pyrophosphate InsP8 acts as an intracellular phosphate signal in Arabidopsis. . Mol. Plant 12::1463–73
     [Crossref] [Google Scholar]
  121. 121.
    Jung JY, Ried MK, Hothorn M, Poirier Y. 2018.. Control of plant phosphate homeostasis by inositol pyrophosphates and the SPX domain. . Curr. Opin. Biotechnol. 49::156–62
     [Crossref] [Google Scholar]
  122. 122.
    Zhu J, Lau K, Puschmann R, Harmel RK, Zhang Y, et al. 2019.. Two bifunctional inositol pyrophosphate kinases/phosphatases control plant phosphate homeostasis. . eLife 8::e43582
     [Crossref] [Google Scholar]
  123. 123.
    Pascual-Ortiz M, Walla E, Fleig U, Saiardi A. 2021.. The PPIP5K family member Asp1 controls inorganic polyphosphate metabolism in S. pombe. . J. Fungi 7::626
     [Crossref] [Google Scholar]
  124. 124.
    Bittner T, Wittwer C, Hauke S, Wohlwend D, Mundinger S, et al. 2020.. Photolysis of caged inositol pyrophosphate InsP8 directly modulates intracellular Ca2+ oscillations and controls C2AB domain localization. . J. Am. Chem. Soc. 142::10606–11
     [Crossref] [Google Scholar]
  125. 125.
    Machkalyan G, Trieu P, Petrin D, Hebert TE, Miller GJ. 2016.. PPIP5K1 interacts with the exocyst complex through a C-terminal intrinsically disordered domain and regulates cell motility. . Cell Signal. 28::401–11
     [Crossref] [Google Scholar]
  126. 126.
    Gokhale NA, Zaremba A, Janoshazi AK, Weaver JD, Shears SB. 2013.. PPIP5K1 modulates ligand competition between diphosphoinositol polyphosphates and PtdIns(3,4,5)P3 for polyphosphoinositide-binding domains. . Biochem. J. 453::413–26
     [Crossref] [Google Scholar]
  127. 127.
    Sahu S, Wang Z, Jiao X, Gu C, Jork N, et al. 2020.. InsP7 is a small-molecule regulator of NUDT3-mediated mRNA decapping and processing-body dynamics. . PNAS 117::19245–53
     [Crossref] [Google Scholar]
  128. 128.
    Wang H, Godage HY, Riley AM, Weaver JD, Shears SB, Potter BVL. 2014.. Synthetic inositol phosphate analogs reveal that PPIP5K2 has a surface-mounted substrate capture site that is a target for drug discovery. . Chem. Biol. 21::689–99
     [Crossref] [Google Scholar]
  129. 129.
    Zhu Q, Ghoshal S, Tyagi R, Chakraborty A. 2017.. Global IP6K1 deletion enhances temperature modulated energy expenditure which reduces carbohydrate and fat induced weight gain. . Mol. Metab. 6::73–85
     [Crossref] [Google Scholar]
  130. 130.
    Zhou Y, Mukherjee S, Huang D, Chakraborty M, Gu C, et al. 2022.. Development of novel IP6K inhibitors for the treatment of obesity and obesity-induced metabolic dysfunctions. . J. Med. Chem. 65::6869–87
     [Crossref] [Google Scholar]
  131. 131.
    Liao G, Ye W, Heitmann T, Ernst G, DePasquale M, et al. 2021.. Identification of small-molecule inhibitors of human inositol hexakisphosphate kinases by high-throughput screening. . ACS Pharmacol. Transl. Sci. 4::780–89
     [Crossref] [Google Scholar]
  132. 132.
    Wormald MM, Ernst G, Wei H, Barrow JC. 2019.. Synthesis and characterization of novel isoform-selective IP6K1 inhibitors. . Bioorg. Med. Chem. Lett. 29::126628
     [Crossref] [Google Scholar]
  133. 133.
    Gu C, Stashko MA, Puhl-Rubio AC, Chakraborty M, Chakraborty A, et al. 2019.. Inhibition of inositol polyphosphate kinases by quercetin and related flavonoids: a structure–activity analysis. . J. Med. Chem. 62::1443–54
     [Crossref] [Google Scholar]
  134. 134.
    Luo HR, Huang YE, Chen JC, Saiardi A, Iijima M, et al. 2003.. Inositol pyrophosphates mediate chemotaxis in Dictyostelium via pleckstrin homology domain-PtdIns(3,4,5)P3 interactions. . Cell 114::559–72
     [Crossref] [Google Scholar]
  135. 135.
    Morgan JAM, Singh A, Kurz L, Nadler-Holly M, Penkert M, et al. 2022.. Pyrophosphoproteomics: extensive protein pyrophosphorylation revealed in human cell lines. . bioRxiv 2022.11.11.516170. https://doi.org/10.1101/2022.11.11.516170
  136. 136.
    Yang S, Jin S, Xian H, Zhao Z, Wang L, et al. 2023.. Metabolic enzyme UAP1 mediates IRF3 pyrophosphorylation to facilitate innate immune response. . Mol. Cell 83::298–313.e8
     [Crossref] [Google Scholar]
/content/journals/10.1146/annurev-biochem-030222-121901
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Inositol Pyrophosphates as Versatile Metabolic Messengers
Annual Review of Biochemistry 93, 317 (2024); https://doi.org/10.1146/annurev-biochem-030222-121901
/content/journals/10.1146/annurev-biochem-030222-121901
/content/journals/10.1146/annurev-biochem-030222-121901
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