Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Inositol derivatives: evolution and functions

Nature Reviews Molecular Cell Biology volume 9, pages 151–161 (2008)Cite this article

Key Points

  • Inositols are ancient molecules that were probably first made by a common ancestor of Archaea and Eukarya more than 2,000 million years ago. They are used by relatively few Bacteria.The glycerophosphate backbones of the inositol lipids of Archaea and Eukarya have opposite configurations: sn-glycerol 1-phosphate and 3-phosphate, respectively.

  • Phosphorylated derivatives of PtdIns (PtdInsPns) and inositol polyphosphates (and their pyrophosphorylated derivatives) are only found in — and are ubiquitous in — eukaryotes, suggesting that their origins were a eukaryotic common ancestor.

  • All eukaryotes use PtdInsPns to regulate diverse aspects of membrane trafficking and interaction.The receptor-controlled phosphoinositide-3-kinase and phosphoinositidase C–Ins(1,4,5)P3–Ca2+ signalling pathways appear to have evolved relatively late, in a common ancestor of the 'Metazoa plus Amoebozoa' domain of the eukaryote crown group.

  • Further studies are needed to understand the emerging functions of diverse inositol polyphosphates (and their pyrophosphorylated derivatives).

Abstract

Current research on inositols mainly focuses on myo-inositol (Ins) derivatives in eukaryotic cells, and in particular on the many roles of Ins phospholipids and polyphosphorylated Ins derivatives. However, inositols and their derivatives are more versatile than this — they have acquired diverse functions over the course of evolution. Given the central involvement of primordial bacteria and archaea in the emergence of eukaryotes, what is the status of inositol derivatives in these groups of organisms, and how might inositol, inositol lipids and inositol phosphates have become ubiquitous constituents of eukaryotes? And how, later, might the multifarious functions of inositol derivatives have emerged during eukaryote diversification?

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The diversity and nomenclature of inositols and their derivatives.
Figure 2: Metabolic pathways for the synthesis of inositol derivatives.
Figure 3: Examples of Ins-containing phospholipid structures.
Figure 4: Development of the diverse usage of Ins derivatives through evolution.

References

  1. Stieglitz, K. A., Yang, H., Roberts, M. F. & Stec, B. Reaching for mechanistic consensus across life kingdoms: structure and insights into catalysis of the myo-inositol-1-phosphate synthase (mIPS) from Archaeoglobus fulgidus. Biochemistry 44, 213–224 (2005).

    CAS  PubMed  Google Scholar 

  2. Majumder, A. L., Chatterjee, A., Dastidar, K. G. & Majee, M. Diversification and evolution of L-myo-inositol 1-phosphate synthase. FEBS Lett. 553, 3–10 (2003).

    CAS  PubMed  Google Scholar 

  3. Stieglitz, K. A., Roberts, M. F., Li, W. & Stec, B. Crystal structure of the tetrameric inositol 1-phosphate phosphatase (TM1415) from the hyperthermophile, Thermotoga maritima. FEBS J. 274, 2461–2469 (2007).

    CAS  PubMed  Google Scholar 

  4. Hipps, P. P., Sehgal, R. K., Holland, W. H. & Sherman, W. R. Identification and partial characterization of inositol: NAD+ epimerase and inosose: NAD(P)H reductase from the fat body of the American cockroach Periplaneta americana. Biochemistry 12, 4705–4712 (1973).

    CAS  Google Scholar 

  5. Poole, A. M. & Penny, D. Evaluating hypotheses for the origin of eukaryotes. Bioessays 29, 74–84 (2007).

    PubMed  Google Scholar 

  6. Gribaldo, S. & Brochier-Armanet, C. The origin and evolution of Archaea: a state of the art. Philos. Trans. R. Soc. Lond. B Biol. Sci. 361, 1007–1022 (2006). A detailed analysis of the origins and phylogeny of the Archaea.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Raven, J. A. & Allen, J. F. Genomics and chloroplast evolution: what did cyanobacteria do for plants? Genome Biol. 4, 2091–2094 (2003).

    Google Scholar 

  8. Dyall, S. D., Brown, M. T. & Johnson, P. J. Ancient invasions: from endosymbionts to organelles. Science 304, 253–257 (2004).

    CAS  PubMed  Google Scholar 

  9. Woese, C. R. The archaeal concept and the world it lives in: a retrospective. Photosynth. Res. 80, 361–372 (2004).

    CAS  PubMed  Google Scholar 

  10. Koga, Y. & Morii, H. Biosynthesis of ether-type polar lipids in archaea and evolutionary considerations. Microbiol. Mol. Biol. Rev. 71, 97–120 (2007). Authoritative analysis of the biosynthesis and evolution of the diradylGro1P-based phospholipids of archaea.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Pereto, J., Lopez-Garcia, P. & Moreira, D. Ancestral lipid biosynthesis and early membrane evolution. Trends Biochem. Sci. 29, 469–477 (2004). Critical discussion of the puzzle of how Archaea came to have phospholipids with an opposite stereochemistry to the Bacteria and Eukarya.

    CAS  PubMed  Google Scholar 

  12. Deretic, V. et al. Phosphoinositides in phagolysosome and autophagosome biogenesis. Biochem. Soc. Symp. 74, 141–148 (2007).

    CAS  Google Scholar 

  13. Vercellone, A., Nigou, J. & Puzo, G. Relationships between the structure and the roles of lipoarabinomannans and related glycoconjugates in tuberculosis pathogenesis. Front. Biosci. 3, e149–e163 (1998).

    CAS  PubMed  Google Scholar 

  14. Jackson, M., Crick, D. C. & Brennan, P. J. Phosphatidylinositol is an essential phospholipid of mycobacteria. J. Biol. Chem. 275, 30092–30099 (2000).

    CAS  Google Scholar 

  15. Michell, R. H. Evolution of the diverse biological roles of inositols. Biochem. Soc. Symp. 74, 223–246 (2007).

    CAS  Google Scholar 

  16. Daiyasu, H. et al. A study of archaeal enzymes involved in polar lipid synthesis linking amino acid sequence information, genomic contexts and lipid composition. Archaea 1, 399–410 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Tenchov, B., Vescio, E. M., Sprott, G. D., Zeidel, M. L. & Mathai, J. C. Salt tolerance of archaeal extremely halophilic lipid membranes. J. Biol. Chem. 281, 10016–10023 (2006).

    CAS  PubMed  Google Scholar 

  18. Daiyasu, H., Hiroike, T., Koga, Y. & Toh, H. Analysis of membrane stereochemistry with homology modeling of sn-glycerol-1-phosphate dehydrogenase. Protein Eng. 15, 987–995 (2002).

    CAS  PubMed  Google Scholar 

  19. Nishihara, M., Utagawa, M., Akutsu, H. & Koga, Y. Archaea contain a novel diether phosphoglycolipid with a polar head group identical to the conserved core of eucaryal glycosyl phosphatidylinositol. J. Biol. Chem. 267, 12432–12435 (1992).

    CAS  PubMed  Google Scholar 

  20. Rodionov, D. A. et al. Genomic identification and in vitro reconstitution of a complete biosynthetic pathway for the osmolyte di-myo-inositol-phosphate. Proc. Natl Acad. Sci. USA 104, 4279–4284 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Borges, N. et al. Biosynthetic pathways of inositol and glycerol phosphodiesters used by the hyperthermophile Archaeoglobus fulgidus in stress adaptation. J. Bacteriol. 188, 8128–8135 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Nesbo, C. L., L'Haridon, S., Stetter, K. O. & Doolittle, W. F. Phylogenetic analyses of two “archaeal” genes in Thermotoga maritima reveal multiple transfers between archaea and bacteria. Mol. Biol. Evol. 18, 362–375 (2001). Demonstrates that MIPS is widespread in archaea, and that its occurrence in miscellaneous bacteria is likely to be a consequence of multiple transfers of archaeal MIPS genes to bacteria.

    CAS  PubMed  Google Scholar 

  23. Wright, E. M. & Turk, E. The sodium/glucose cotransport family SLC5. Pflugers Arch. 447, 510–518 (2004).

    CAS  PubMed  Google Scholar 

  24. Fahey, R. C. Novel thiols of prokaryotes. Annu. Rev. Microbiol. 55, 333–356 (2001).

    CAS  PubMed  Google Scholar 

  25. Michell, R. H., Heath, V. L., Lemmon, M. A. & Dove, S. K. Phosphatidylinositol 3,5-bisphosphate: metabolism and cellular functions. Trends Biochem. Sci. 31, 52–63 (2006).

    CAS  PubMed  Google Scholar 

  26. Ongun, A., Thomson, W. W. & Mudd, J. B. Lipid composition of chloroplasts isolated by aqueous and nonaqueous techniques. J. Lipid Res. 9, 409–415 (1968).

    CAS  PubMed  Google Scholar 

  27. Majumder, A. L., Johnson, M. D. & Henry, S. A. 1L-myo-inositol-1-phosphate synthase. Biochim. Biophys. Acta 1348, 245–256 (1997).

    CAS  PubMed  Google Scholar 

  28. Vignais, P. M., Vignais, P. V. & Lehninger, A. L. Restoration of ATP-induced contraction of “aged” mitochondria by phosphatidyl inositol. Biochem. Biophys. Res. Commun. 11, 313–318 (1963).

    CAS  PubMed  Google Scholar 

  29. Luis Villar, J., Puigbo, P. & Riera-Codina, M. Analysis of highly phosphorylated inositols in avian and crocodilian erythrocytes. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 135, 169–175 (2003).

    PubMed  Google Scholar 

  30. Val, A. L. Organic phosphates in the red blood cells of fish. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 125, 417–435 (2000).

    CAS  PubMed  Google Scholar 

  31. Chauvin, T. R. & Griswold, M. D. Characterization of the expression and regulation of genes necessary for myo-inositol biosynthesis and transport in the seminiferous epithelium. Biol. Reprod. 70, 744–751 (2004).

    CAS  PubMed  Google Scholar 

  32. Antonsson, B. Phosphatidylinositol synthase from mammalian tissues. Biochim. Biophys. Acta 1348, 179–186 (1997).

    CAS  PubMed  Google Scholar 

  33. Tanaka, S., Nikawa, J., Imai, H., Yamashita, S. & Hosaka, K. Molecular cloning of rat phosphatidylinositol synthase cDNA by functional complementation of the yeast Saccharomyces cerevisiae pis mutation. FEBS Lett. 393, 89–92 (1996).

    CAS  PubMed  Google Scholar 

  34. Nunez, L. R. & Henry, S. A. Regulation of 1D-myo-inositol-3-phosphate synthase in yeast. Subcell. Biochem. 39, 135–156 (2006).

    PubMed  Google Scholar 

  35. Carman, G. M. & Kersting, M. C. Phospholipid synthesis in yeast: regulation by phosphorylation. Biochem. Cell Biol. 82, 62–70 (2004).

    CAS  PubMed  Google Scholar 

  36. Eagle, H., Oyama, V. I., Levy, M. & Freeman, A. E. Myoinositol as an essential growth factor for normal and malignant cells in culture. J. Biol. Chem. 226, 191–206 (1957).

    CAS  PubMed  Google Scholar 

  37. Jackson, M. J. & Shin, S. Inositol as a growth factor for mammalian cells in culture. Cold Spring Harbor Conf. Cell Prolif. 9A, 75–86 (1982).

    Google Scholar 

  38. Holub, B. J. The nutritional significance, metabolism, and function of myo-inositol and phosphatidylinositol in health and disease. Adv. Nutr. Res. 4, 107–141 (1982).

    CAS  PubMed  Google Scholar 

  39. Hayashi, E., Maeda, T. & Tomita, T. The effect of myo-inositol deficiency on lipid metabolism in rats. II. The mechanism of triacylglycerol accumulation in the liver of myo-inositol-deficient rats. Biochim. Biophys. Acta 360, 146–155 (1974).

    CAS  PubMed  Google Scholar 

  40. Fedorov, A. & Hartman, H. What does the microsporidian E. cuniculi tell us about the origin of the eukaryotic cell? J. Mol. Evol. 59, 695–702 (2004).

    CAS  PubMed  Google Scholar 

  41. Hartman, H. & Fedorov, A. The origin of the eukaryotic cell: a genomic investigation. Proc. Natl Acad. Sci. USA 99, 1420–1425 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Yancey, P. H. Organic osmolytes as compatible, metabolic and counteracting cytoprotectants in high osmolarity and other stresses. J. Exp. Biol. 208, 2819–2830 (2005). An excellent summary of the many molecules, including inositols and their derivatives, that can act as 'compatible solutes' and the extraordinary variety of organisms and environments in which these molecules have these roles.

    CAS  PubMed  Google Scholar 

  43. Yancey, P. H., Blake, W. R. & Conley, J. Unusual organic osmolytes in deep-sea animals: adaptations to hydrostatic pressure and other perturbants. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 133, 667–676 (2002).

    PubMed  Google Scholar 

  44. Das-Chatterjee, A. et al. Introgression of a novel salt-tolerant L-myo-inositol 1-phosphate synthase from Porteresia coarctata (Roxb.) Tateoka (PcINO1) confers salt tolerance to evolutionary diverse organisms. FEBS Lett. 580, 3980–3988 (2006). Remarkably, shows that just allowing diverse cells to make large amounts of Ins confers protection against salt stress.

    CAS  PubMed  Google Scholar 

  45. Zhou, C. & Cammarata, P. R. Cloning the bovine Na+/myo-inositol cotransporter gene and characterization of an osmotic responsive promoter. Exp. Eye Res. 65, 349–363 (1997).

    CAS  PubMed  Google Scholar 

  46. Kitamura, H. et al. Inhibition of myo-inositol transport causes acute renal failure with selective medullary injury in the rat. Kidney Int. 53, 146–153 (1998).

    CAS  PubMed  Google Scholar 

  47. Berry, G. T. et al. Loss of murine Na+/myo-inositol cotransporter leads to brain myo-inositol depletion and central apnea. J. Biol. Chem. 278, 18297–18302 (2003).

    CAS  PubMed  Google Scholar 

  48. Chau, J. F., Lee, M. K., Law, J. W., Chung, S. K. & Chung, S. S. Sodium/myo-inositol cotransporter-1 is essential for the development and function of the peripheral nerves. FASEB J. 19, 1887–1889 (2005).

    CAS  PubMed  Google Scholar 

  49. McLaurin, J. et al. Cyclohexanehexol inhibitors of Aβ aggregation prevent and reverse Alzheimer phenotype in a mouse model. Nature Med. 12, 801–808 (2006).

    CAS  PubMed  Google Scholar 

  50. Fenili, D., Brown, M., Rappaport, R. & McLaurin, J. Properties of scyllo-inositol as a therapeutic treatment of AD-like pathology. J. Mol. Med. 85, 603–611 (2007).

    CAS  PubMed  Google Scholar 

  51. Townsend, M. et al. Orally available compound prevents deficits in memory caused by the Alzheimer amyloid-β oligomers. Ann. Neurol. 60, 668–676 (2006).

    CAS  PubMed  Google Scholar 

  52. Gardocki, M. E., Jani, N. & Lopes, J. M. Phosphatidylinositol biosynthesis: biochemistry and regulation. Biochim. Biophys. Acta 1735, 89–100 (2005).

    CAS  PubMed  Google Scholar 

  53. Michell, R. H. Inositol phospholipids and cell surface receptor function. Biochim. Biophys. Acta 415, 81–47 (1975).

    CAS  PubMed  Google Scholar 

  54. D'Angelo, G. et al. Glycosphingolipid synthesis requires FAPP2 transfer of glucosylceramide. Nature 449, 62–67 (2007).

    CAS  PubMed  Google Scholar 

  55. Balla, A. & Balla, T. Phosphatidylinositol 4-kinases: old enzymes with emerging functions. Trends Cell Biol. 16, 351–361 (2006). An excellent analysis of the diversity and multiple functions of the various PtdIns 4-kinases.

    CAS  PubMed  Google Scholar 

  56. Audhya, A., Foti, M. & Emr, S. D. Distinct roles for the yeast phosphatidylinositol 4-kinases, Stt4p and Pik1p, in secretion, cell growth, and organelle membrane dynamics. Mol. Biol. Cell 11, 2673–2689 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Perera, N. M., Michell, R. H. & Dove, S. K. Hypo-osmotic stress activates Plc1p-dependent phosphatidylinositol 4, 5-bisphosphate hydrolysis and inositol hexakisphosphate accumulation in yeast. J. Biol. Chem. 279, 5216–5226 (2004).

    CAS  PubMed  Google Scholar 

  58. Di Paolo, G. & De Camilli, P. Phosphoinositides in cell regulation and membrane dynamics. Nature 443, 651–657 (2006). An excellent summary of the many functions of phosphoinositides in membrane interactions and trafficking.

    CAS  PubMed  Google Scholar 

  59. Heck, J. N. et al. A conspicuous connection: structure defines function for the phosphatidylinositol-phosphate kinase family. Crit. Rev. Biochem. Mol. Biol. 42, 15–39 (2007).

    CAS  PubMed  Google Scholar 

  60. Rebecchi, M. J. & Pentyala, S. N. Structure, function, and control of phosphoinositide-specific phospholipase C. Physiol. Rev. 80, 1291–1335 (2000). An excellent analysis of the complex biology of the PICs.

    CAS  PubMed  Google Scholar 

  61. Patterson, R. L., van Rossum, D. B., Nikolaidis, N., Gill, D. L. & Snyder, S. H. Phospholipase C-γ: diverse roles in receptor-mediated calcium signaling. Trends Biochem. Sci. 30, 688–697 (2005).

    CAS  PubMed  Google Scholar 

  62. Bunney, T. D. & Katan, M. Phospholipase C ɛ: linking second messengers and small GTPases. Trends Cell Biol. 16, 640–648 (2006).

    CAS  PubMed  Google Scholar 

  63. Saunders, C. M., Swann, K. & Lai, F. A. PLCζ, a sperm-specific PLC and its potential role in fertilization. Biochem. Soc. Symp. 74, 23–36 (2007).

    CAS  Google Scholar 

  64. Meijer, H. J. & Govers, F. Genomewide analysis of phospholipid signaling genes in Phytophthora spp.: novelties and a missing link. Mol. Plant Microbe Interact. 19, 1337–1347 (2006).

    CAS  PubMed  Google Scholar 

  65. Einspahr, K. J., Peeler, T. C. & Thompson, G. A. Jr. Rapid changes in polyphosphoinositide metabolism associated with the response of Dunaliella salina to hypoosmotic shock. J. Biol. Chem. 263, 5775–5779 (1988).

    CAS  PubMed  Google Scholar 

  66. Mikoshiba, K. The IP3 receptor/Ca2+ channel and its cellular function. Biochem. Soc. Symp. 74, 9–22 (2007).

    CAS  Google Scholar 

  67. Sorrentino, V., Barone, V. & Rossi, D. Intracellular Ca2+ release channels in evolution. Curr. Opin. Genet. Dev. 10, 662–667 (2000).

    CAS  PubMed  Google Scholar 

  68. Traynor, D., Milne, J. L., Insall, R. H. & Kay, R. R. Ca2+ signalling is not required for chemotaxis in Dictyostelium. EMBO J. 19, 4846–4854 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Belde, P. J., Vossen, J. H., Borst-Pauwels, G. W. & Theuvenet, A. P. Inositol 1,4,5-trisphosphate releases Ca2+ from vacuolar membrane vesicles of Saccharomyces cerevisiae. FEBS Lett. 323, 113–118 (1993).

    CAS  PubMed  Google Scholar 

  70. Muir, S. R. & Sanders, D. Inositol 1,4,5-trisphosphate-sensitive Ca2+ release across nonvacuolar membranes in cauliflower. Plant Physiol. 114, 1511–1521 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Seeds, A. M., Frederick, J. P., Tsui, M. M. & York, J. D. Roles for inositol polyphosphate kinases in the regulation of nuclear processes and developmental biology. Adv. Enzyme Regul. 47, 10–25 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Bennett, M., Onnebo, S. M., Azevedo, C. & Saiardi, A. Inositol pyrophosphates: metabolism and signaling. Cell. Mol. Life Sci. 63, 552–564 (2006). Reviews the novel biology being revealed by examination of inositol pyrophosphates.

    CAS  PubMed  Google Scholar 

  73. Otto, J. C., Kelly, P., Chiou, S. T. & York, J. D. Alterations in an inositol phosphate code through synergistic activation of a G protein and inositol phosphate kinases. Proc. Natl Acad. Sci. USA 104, 15653–15658 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Simonsen, A., Wurmser, A. E., Emr, S. D. & Stenmark, H. The role of phosphoinositides in membrane transport. Curr. Opin. Cell Biol. 13, 485–492 (2001).

    CAS  PubMed  Google Scholar 

  75. Nicot, A. S. et al. The phosphoinositide kinase PIKfyve/Fab1p regulates terminal lysosome maturation in Caenorhabditis elegans. Mol. Biol. Cell 17, 3062–3074 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Rusten, T. E. et al. Fab1 phosphatidylinositol 3-phosphate 5-kinase controls trafficking but not silencing of endocytosed receptors. Mol. Biol. Cell 17, 3989–4001 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Efe, J. A., Botelho, R. J. & Emr, S. D. The Fab1 phosphatidylinositol kinase pathway in the regulation of vacuole morphology. Curr. Opin. Cell Biol. 17, 402–408 (2005).

    CAS  PubMed  Google Scholar 

  78. Hayakawa, A., Hayes, S., Leonard, D., Lambright, D. & Corvera, S. Evolutionarily conserved structural and functional roles of the FYVE domain. Biochem. Soc. Symp. 74, 95–105 (2007).

    CAS  Google Scholar 

  79. Hernandez, L. D., Hueffer, K., Wenk, M. R. & Galan, J. E. Salmonella modulates vesicular traffic by altering phosphoinositide metabolism. Science 304, 1805–1807 (2004).

    CAS  PubMed  Google Scholar 

  80. Wei, Z., Zenewicz, L. A. & Goldfine, H. Listeria monocytogenes phosphatidylinositol-specific phospholipase C has evolved for virulence by greatly reduced activity on GPI anchors. Proc. Natl Acad. Sci. USA 102, 12927–12931 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Goldfine, H. & Wadsworth, S. J. Macrophage intracellular signaling induced by Listeria monocytogenes. Microbes Infect. 4, 1335–1343 (2002).

    CAS  PubMed  Google Scholar 

  82. Vanhaesebroeck, B., Ali, K., Bilancio, A., Geering, B. & Foukas, L. C. Signalling by PI3K isoforms: insights from gene-targeted mice. Trends Biochem. Sci. 30, 194–204 (2005).

    CAS  PubMed  Google Scholar 

  83. Neufeld, T. P. Body building: regulation of shape and size by PI3K/TOR signaling during development. Mech. Dev. 120, 1283–1296 (2003).

    CAS  PubMed  Google Scholar 

  84. Putnam, N. H. et al. Sea anemone genome reveals ancestral eumetazoan gene repertoire and genomic organization. Science 317, 86–94 (2007).

    CAS  PubMed  Google Scholar 

  85. Sasaki, A. T. & Firtel, R. A. Regulation of chemotaxis by the orchestrated activation of Ras, PI3K, and TOR. Eur. J. Cell Biol. 85, 873–895 (2006).

    CAS  PubMed  Google Scholar 

  86. Andrew, N. & Insall, R. H. Chemotaxis in shallow gradients is mediated independently of PtdIns 3-kinase by biased choices between random protrusions. Nature Cell Biol. 9, 193–200 (2007).

    CAS  PubMed  Google Scholar 

  87. Hoeller, O. & Kay, R. R. Chemotaxis in the absence of PIP3 gradients. Curr. Biol. 17, 813–817 (2007).

    CAS  PubMed  Google Scholar 

  88. Mitra, P. et al. A novel phosphatidylinositol(3,4,5)P3 pathway in fission yeast. J. Cell Biol. 166, 205–211 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Shears, S. B. Assessing the omnipotence of inositol hexakisphosphate. Cell Signal. 13, 151–158 (2001).

    CAS  PubMed  Google Scholar 

  90. Wong, N. S. et al. The inositol phosphates in WRK1 rat mammary tumour cells. Biochem. J. 286, 459–468 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Irvine, R. F. & Schell, M. J. Back in the water: the return of the inositol phosphates. Nature Rev. Mol. Cell Biol. 2, 327–338 (2001). An authoritative and detailed discussion of inositol polyphosphates and pyrophosphates.

    CAS  Google Scholar 

  92. York, J. D. Regulation of nuclear processes by inositol polyphosphates. Biochim. Biophys. Acta 1761, 552–559 (2006).

    CAS  PubMed  Google Scholar 

  93. French, P. J. et al. Changes in the levels of inositol lipids and phosphates during the differentiation of HL60 promyelocytic cells towards neutrophils or monocytes. Proc. Biol. Sci. 245, 193–201 (1991).

    CAS  PubMed  Google Scholar 

  94. Menniti, F. S., Oliver, K. G., Putney, J. W. Jr & Shears, S. B. Inositol phosphates and cell signaling: new views of InsP5 and InsP6. Trends Biochem. Sci. 18, 53–56 (1993).

    CAS  PubMed  Google Scholar 

  95. Macbeth, M. R. et al. Inositol hexakisphosphate is bound in the ADAR2 core and required for RNA editing. Science 309, 1534–1539 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Tan, X. et al. Mechanism of auxin perception by the TIR1 ubiquitin ligase. Nature 446, 640–645 (2007).

    CAS  PubMed  Google Scholar 

  97. Stephens, L. R. & Irvine, R. F. Stepwise phosphorylation of myo-inositol leading to myo-inositol hexakisphosphate in Dictyostelium. Nature 346, 580–583 (1990). Reports a direct route from Ins to InsP 6 in D. discoideum , which is still the only organism in which this has been reported, for unknown reasons.

    CAS  PubMed  Google Scholar 

  98. Shears, S. B. Understanding the biological significance of diphosphoinositol polyphosphates ('inositol pyrophosphates'). Biochem. Soc. Symp. 74, 211–221 (2007).

    CAS  Google Scholar 

  99. Mulugu, S. et al. A conserved family of enzymes that phosphorylate inositol hexakisphosphate. Science 316, 106–109 (2007).

    CAS  PubMed  Google Scholar 

  100. Seeds, A. M., Bastidas, R. J. & York, J. D. Molecular definition of a novel inositol polyphosphate metabolic pathway initiated by inositol 1,4,5-trisphosphate 3-kinase activity in Saccharomyces cerevisiae. J. Biol. Chem. 280, 27654–27661 (2005).

    CAS  PubMed  Google Scholar 

  101. Saiardi, A., Resnick, A. C., Snowman, A. M., Wendland, B. & Snyder, S. H. Inositol pyrophosphates regulate cell death and telomere length through phosphoinositide 3-kinase-related protein kinases. Proc. Natl Acad. Sci. USA 102, 1911–1914 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Illies, C. et al. Requirement of inositol pyrophosphates for full exocytotic capacity in pancreatic β cells. Science 318, 1299–1302 (2007).

    CAS  PubMed  Google Scholar 

  103. York, S. J., Armbruster, B. N., Greenwell, P., Petes, T. D. & York, J. D. Inositol diphosphate signaling regulates telomere length. J. Biol. Chem. 280, 4264–4269 (2005).

    CAS  PubMed  Google Scholar 

  104. Saiardi, A., Bhandari, R., Resnick, A. C., Snowman, A. M. & Snyder, S. H. Phosphorylation of proteins by inositol pyrophosphates. Science 306, 2101–2105 (2004).

    CAS  PubMed  Google Scholar 

  105. Bhandari, R. et al. Protein pyrophosphorylation by inositol pyrophosphates is a posttranslational event. Proc. Natl Acad. Sci. USA 104, 15305–15310 (2007). Reports the pyrophosphorylation of phosphoserine residues by phosphate transfer from inositol pyrophosphates — a new covalent modification of proteins.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Cosgrove, D. J. & Tate, M. E. in Inositol Phosphates: their Chemistry, Biochemistry and Physiology (Elsevier, London, 1980).

    Google Scholar 

  107. Turner, B. L., Paphazy, M. J., Haygarth, P. M. & McKelvie, I. D. Inositol phosphates in the environment. Philos. Trans. R. Soc. Lond. B Biol. Sci. 357, 449–469 (2002). Emphasizes the enormous quantities of inositol polyphosphates, based on several different inositols, that are present in the environment.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Raboy, V. Seeds for a better future: 'low phytate' grains help to overcome malnutrition and reduce pollution. Trends Plant Sci. 6, 458–462 (2001).

    CAS  PubMed  Google Scholar 

  109. Martin, J. B., Laussmann, T., Bakker-Grunwald, T., Vogel, G. & Klein, G. neo-inositol polyphosphates in the amoeba Entamoeba histolytica. J. Biol. Chem. 275, 10134–10140 (2000).

    CAS  PubMed  Google Scholar 

  110. Ferguson, M. A. et al. The GPI biosynthetic pathway as a therapeutic target for African sleeping sickness. Biochim. Biophys. Acta 1455, :327–340 (1999).

    CAS  PubMed  Google Scholar 

  111. Pittet, M. & Conzelmann, A. Biosynthesis and function of GPI proteins in the yeast Saccharomyces cerevisiae. Biochim. Biophys. Acta 1771, 405–420 (2007).

    CAS  PubMed  Google Scholar 

  112. Shams-Eldin, H. et al. The GPI1 homologue from Plasmodium falciparum complements a Saccharomyces cerevisiae GPI1 anchoring mutant. Mol. Biochem. Parasitol. 120, 73–81 (2002).

    CAS  PubMed  Google Scholar 

  113. Eisenhaber, B., Bork, P. & Eisenhaber, F. Post-translational GPI lipid anchor modification of proteins in kingdoms of life: analysis of protein sequence data from complete genomes. Protein Eng. 14, 17–25 (2001).

    CAS  PubMed  Google Scholar 

  114. Futerman, A. H., Low, M. G., Ackermann, K. E., Sherman, W. R. & Silman, I. Identification of covalently bound inositol in the hydrophobic membrane-anchoring domain of Torpedo acetylcholinesterase. Biochem. Biophys. Res. Commun. 129, 312–317 (1985).

    CAS  PubMed  Google Scholar 

  115. Ikezawa, H. Glycosylphosphatidylinositol (GPI)-anchored proteins. Biol. Pharm. Bull. 25, 409–417 (2002).

    CAS  PubMed  Google Scholar 

  116. Baldauf, S. L. The deep roots of eukaryotes. Science 300, 1703–1706 (2003).

    CAS  PubMed  Google Scholar 

  117. Morrison, H. G. et al. Genomic minimalism in the early diverging intestinal parasite Giardia lamblia. Science 317, 1921–1926 (2007).

    CAS  PubMed  Google Scholar 

  118. Kuspa, A. & Loomis, W. F. The genome of Dictyostelium discoideum. Methods Mol. Biol. 346, 15–28 (2006).

    CAS  PubMed  Google Scholar 

  119. Richards, T. A. & Cavalier-Smith, T. Myosin domain evolution and the primary divergence of eukaryotes. Nature 436, 1113–1118 (2005).

    CAS  PubMed  Google Scholar 

  120. Hedges, S. B., Blair, J. E., Venturi, M. L. & Shoe, J. L. A molecular timescale of eukaryote evolution and the rise of complex multicellular life. BMC Evol. Biol. 4, 2 (2004). A detailed discussion of the inferred temporal sequence of eukaryote diversification.

    PubMed  PubMed Central  Google Scholar 

  121. Steenkamp, E. T., Wright, J. & Baldauf, S. L. The protistan origins of animals and fungi. Mol. Biol. Evol. 23, 93–106 (2006).

    CAS  PubMed  Google Scholar 

  122. Posternak, T. The Cyclitols (Editions Scientifiques Hermann, Paris, 1965).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Biosciences, University of Birmingham, Birmingham, B15 2TT, UK

    Robert H. Michell

Authors
  1. Robert H. Michell
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

FURTHER INFORMATION

Choanobase web site

Shears laboratory web site

Glossary

Archaea

The third kingdom of life, distinct from Bacteria and Eukarya. Archaea are unicellular and grow in diverse environments that are often physically extreme. Their DNA replication apparatus is more similar to Eukarya than to Bacteria.

Eukarya

The kingdom of life that is characterized by cells that have nuclei and other membrane-bounded organelles. Eukarya include animals, plants, fungi, amoebozoans and numerous phyla of unicellular organisms.

α-proteobacteria

An ancient bacterial phylogenetic group that includes most phototrophic genera, several genera that metabolize 1-carbon compounds (such as Methylobacterium), plant symbionts (such as Rhizobia) and the Rickettsiaceae (including several pathogens). α-proteobacteria are the ancestors of mitochondria.

Cyanobacteria

Also known as Cyanophyta and blue-green algae. An ancient phylogenetic group of aquatic bacteria that obtain their energy through photosynthesis. Cyanobacteria are the ancestors of chloroplasts.

Actinobacteria

Also known as Actinomycetes. This large group of high G+C Gram-positive bacteria includes pathogenic mycobacteria and soil organisms that decompose organic material. Actinobacteria are sources of commercially valuable secondary metabolites, including antibiotics.

Phospholipid headgroup

The hydrophilic headgroup of a membrane phospholipid that is exposed at the membrane surface.

Halophilic archaea

Archaea that grow only, or preferentially, in high-salt environments.

Archaetidyl

A backbone structure in archaeal glycerophospholipid that comprises glycerol-1-phosphate modified with isoprane-based long-chain ethers on carbons 2 and 3.

Caldarchaetidyl

A double-headed backbone structure in archaeal glycerophospholipids that comprises two glycerol-1-phosphate groups, each of which is modified with isoprane-based long-chain ethers on carbons 2 and 3.

Hyperthermophilic archaea

Archaea that grow only, or preferentially, at very high temperatures (70–100 °C).

Protists

An informal portmanteau term for the many unicellular eukaryotes that are not animals, plants or fungi.

Choanoflagellates

The closest extant relatives of metazoa and fungi. They are free-living (single-cell or colony-forming) eukaryotes that are ubiquitous in aquatic environments, and typically have an ovoid cell body that has a single apical flagellum surrounded by a collar of microvilli.

Microsporidians

Parasitic fungi, some of which are pathogens of metazoa (such as Encephalitozoon cuniculi, the genome of which has been sequenced), that have extremely reduced genomes and mitochondrial remnants (mitosomes).

Glomerular filtrate

The blood plasma filtrate that emerges from the glomerulus of the mammalian kidney, mainly comprising water and low molecular mass solutes (such as ions, sugars and amino acids) that are actively reabsorbed in later segments of the nephron.

Apicomplexans

A large group of spore-forming protists that are characterized by a unique organelle (the apical complex) and are parasites of animals. Apicomplexans cause diseases such as malaria and cryptosporidiosis.

Ecdysozoa

One of the major groups of animals, which includes both the arthropods and nematodes. Many members of this group regularly shed their cuticle by ecdysis, hence the name Ecdysozoa.

Cnidarians

An ancient phylum of marine organisms with rotational symmetry, of which the anthozoa (including sea anemones and corals) were probably the earliest to diverge.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Michell, R. Inositol derivatives: evolution and functions. Nat Rev Mol Cell Biol 9, 151–161 (2008). https://doi.org/10.1038/nrm2334

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm2334

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing