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MetaCyc Pathway: inositol pyrophosphates biosynthesis
Inferred from experiment

Pathway diagram: inositol pyrophosphates biosynthesis

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Synonyms: diphosphorylated inositol polyphosphates biosynthesis

Superclasses: BiosynthesisSecondary Metabolites BiosynthesisSugar Derivatives BiosynthesisCyclitols Biosynthesis

Some taxa known to possess this pathway include : Homo sapiens, Rattus norvegicus, Saccharomyces cerevisiae

Expected Taxonomic Range: Eukaryota

In the early 1990s, two groups working independently discovered a novel subgroup of the inositol phosphate signaling family in which diphosphate groups are added to D-myo-inositol 1,3,4,5,6-pentakisphosphate and phytate [Stephens93, Menniti93], forming compounds that are now known as "inositol pyrophosphates" or "diphosphoinositol polyphosphates" [Bennett06]. These molecules have been reported to be involved in the regulation of vesicle trafficking [Saiardi02], transcription [El03a], chemotaxis [Luo03], telomere maintenance [York05, Saiardi05], apoptosis [Nagata05, Morrison01], and DNA repair [Luo02a], and to mediate environmental stress responses [Dubois02, Pesesse04, Safrany04, Choi05a].

The concentration of the molecules appear to be tightly regulated with an extremely rapid turnover [Burton09a]. By inhibiting the enzymes that remove the pyrophosphate groups (encoded by NUDT3, NUDT4, NUDT10 and NUDT11) it was possible to calculate that their cellular pools were normally turning over at least 10 times every 40 min [Glennon93].

The pathway that leads to the biosynthesis of inositol pyrophosphates has been illucidated. Two main classes of enzymes are involved in yeast and mammals: 5-kinases (encoded in mammals by IP6K1, IP6K2 and IP6K3, and in yeast by KcsI) [Saiardi99, Saiardi01] and 1/3 kinases (encoded in mammals by PPIP5K1 and PPIP5K2 and in yeast by Vip1) [Mulugu07, Lin09a].

All of these enzymes can phosphorylate phytate, generating either 1D-myoinositol 5-diphosphate 1,2,3,4,6-pentakisphosphate (in the case of IP6K) or a mixture of 1D-myo-inositol 1-diphosphate 2,3,4,5,6-pentakisphosphate and 1D-myo-inositol 3-diphosphate 1,2,4,5,6-pentakisphosphate (in the case of PPIP5K). These compounds, which contain a single pyrophosphate, are also known simply as InsP7. In addition, each enzyme class can continue to phosphorylate the product of the other enzyme class, resulting in a mixture of 1D-myo-inositol 1,5-bis(diphosphate) 2,3,4,6-tetrakisphosphate and 3,5-bisdiphosphoinositol-1D-myo-inositol 2,3,4,6-tetrakisphosphate, also known as InsP8 [Lin09a].

Another inositol pyrophosphate that is found in cells is a diphospho-1D-myo-inositol tetrakisphosphate, whose exact stereomeric structure has not been defined yet. This compound is synthesized from D-myo-inositol 1,3,4,5,6-pentakisphosphate by the three IP6K [Saiardi00a], as well as the inositol 1,3,4,6-tetrakisphosphate 5-kinase ( IPMK) [Saiardi01a].

Superpathways: superpathway of inositol phosphate compounds

Created 28-Oct-2009 by Caspi R, SRI International


Bennett06: Bennett M, Onnebo SM, Azevedo C, Saiardi A (2006). "Inositol pyrophosphates: metabolism and signaling." Cell Mol Life Sci 63(5);552-64. PMID: 16429326

Burton09a: Burton A, Hu X, Saiardi A (2009). "Are inositol pyrophosphates signalling molecules?." J Cell Physiol 220(1);8-15. PMID: 19326391

Caffrey00: 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(17);12730-6. PMID: 10777568

Choi05a: Choi K, Mollapour E, Shears SB (2005). "Signal transduction during environmental stress: InsP8 operates within highly restricted contexts." Cell Signal 17(12);1533-41. PMID: 15936174

Dubois02: Dubois E, Scherens B, Vierendeels F, Ho MM, Messenguy F, Shears SB (2002). "In Saccharomyces cerevisiae, the inositol polyphosphate kinase activity of Kcs1p is required for resistance to salt stress, cell wall integrity, and vacuolar morphogenesis." J Biol Chem 277(26);23755-63. PMID: 11956213

El03a: El Alami M, Messenguy F, Scherens B, Dubois E (2003). "Arg82p is a bifunctional protein whose inositol polyphosphate kinase activity is essential for nitrogen and PHO gene expression but not for Mcm1p chaperoning in yeast." Mol Microbiol 49(2);457-68. PMID: 12828642

Glennon93: Glennon MC, Shears SB (1993). "Turnover of inositol pentakisphosphates, inositol hexakisphosphate and diphosphoinositol polyphosphates in primary cultured hepatocytes." Biochem J 293 ( Pt 2);583-90. PMID: 8343137

Lin09a: Lin H, Fridy PC, Ribeiro AA, Choi JH, Barma DK, Vogel G, Falck JR, Shears SB, York JD, Mayr GW (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(3);1863-72. PMID: 18981179

Luo02a: Luo HR, Saiardi A, Yu H, Nagata E, Ye K, Snyder SH (2002). "Inositol pyrophosphates are required for DNA hyperrecombination in protein kinase c1 mutant yeast." Biochemistry 41(8);2509-15. PMID: 11851397

Luo03: Luo HR, Huang YE, Chen JC, Saiardi A, Iijima M, Ye K, Huang Y, Nagata E, Devreotes P, Snyder SH (2003). "Inositol pyrophosphates mediate chemotaxis in Dictyostelium via pleckstrin homology domain-PtdIns(3,4,5)P3 interactions." Cell 114(5);559-72. PMID: 13678580

Menniti93: Menniti FS, Miller RN, Putney JW, Shears SB (1993). "Turnover of inositol polyphosphate pyrophosphates in pancreatoma cells." J Biol Chem 268(6);3850-6. PMID: 8382679

Morrison01: Morrison BH, Bauer JA, Kalvakolanu DV, Lindner DJ (2001). "Inositol hexakisphosphate kinase 2 mediates growth suppressive and apoptotic effects of interferon-beta in ovarian carcinoma cells." J Biol Chem 276(27);24965-70. PMID: 11337497

Mulugu07: Mulugu S, Bai W, Fridy PC, Bastidas RJ, Otto JC, Dollins DE, Haystead TA, Ribeiro AA, York JD (2007). "A conserved family of enzymes that phosphorylate inositol hexakisphosphate." Science 316(5821);106-9. PMID: 17412958

Nagata05: Nagata E, Luo HR, Saiardi A, Bae BI, Suzuki N, Snyder SH (2005). "Inositol hexakisphosphate kinase-2, a physiologic mediator of cell death." J Biol Chem 280(2);1634-40. PMID: 15533939

Pesesse04: 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(42);43378-81. PMID: 15316027

Safrany04: Safrany ST (2004). "Protocols for regulation and study of diphosphoinositol polyphosphates." Mol Pharmacol 66(6);1585-91. PMID: 15342793

Saiardi00a: Saiardi A, Caffrey JJ, Snyder SH, Shears SB (2000). "The inositol hexakisphosphate kinase family. Catalytic flexibility and function in yeast vacuole biogenesis." J Biol Chem 275(32);24686-92. PMID: 10827188

Saiardi01: Saiardi A, Nagata E, Luo HR, Snowman AM, Snyder SH (2001). "Identification and characterization of a novel inositol hexakisphosphate kinase." J Biol Chem 276(42);39179-85. PMID: 11502751

Saiardi01a: Saiardi A, Nagata E, Luo HR, Sawa A, Luo X, Snowman AM, Snyder SH (2001). "Mammalian inositol polyphosphate multikinase synthesizes inositol 1,4,5-trisphosphate and an inositol pyrophosphate." Proc Natl Acad Sci U S A 98(5);2306-11. PMID: 11226235

Saiardi02: Saiardi A, Sciambi C, McCaffery JM, Wendland B, Snyder SH (2002). "Inositol pyrophosphates regulate endocytic trafficking." Proc Natl Acad Sci U S A 99(22);14206-11. PMID: 12391334

Saiardi05: Saiardi A, Resnick AC, Snowman AM, Wendland B, Snyder SH (2005). "Inositol pyrophosphates regulate cell death and telomere length through phosphoinositide 3-kinase-related protein kinases." Proc Natl Acad Sci U S A 102(6);1911-4. PMID: 15665079

Saiardi99: 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(22);1323-6. PMID: 10574768

Stephens93: Stephens L, Radenberg T, Thiel U, Vogel G, Khoo KH, Dell A, Jackson TR, Hawkins PT, Mayr GW (1993). "The detection, purification, structural characterization, and metabolism of diphosphoinositol pentakisphosphate(s) and bisdiphosphoinositol tetrakisphosphate(s)." J Biol Chem 268(6);4009-15. PMID: 8440693

York05: York SJ, Armbruster BN, Greenwell P, Petes TD, York JD (2005). "Inositol diphosphate signaling regulates telomere length." J Biol Chem 280(6);4264-9. PMID: 15561716

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Bunce93: Bunce CM, French PJ, Allen P, Mountford JC, Moor B, Greaves MF, Michell RH, Brown G (1993). "Comparison of the levels of inositol metabolites in transformed haemopoietic cells and their normal counterparts." Biochem J 289 ( Pt 3);667-73. PMID: 8435066

Chadwick92: Chadwick CC, Timerman AP, Saito A, Mayrleitner M, Schindler H, Fleischer S (1992). "Structural and functional characterization of an inositol polyphosphate receptor from cerebellum." J Biol Chem 267(5);3473-81. PMID: 1371119

Chang02a: Chang SC, Miller AL, Feng Y, Wente SR, Majerus PW (2002). "The human homolog of the rat inositol phosphate multikinase is an inositol 1,3,4,6-tetrakisphosphate 5-kinase." J Biol Chem 277(46);43836-43. PMID: 12223481

Choi07: Choi JH, Williams J, Cho J, Falck JR, 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(42);30763-75. PMID: 17702752

Coelho05: Coelho CM, Tsai SM, Vitorello VA (2005). "Dynamics of inositol phosphate pools (tris-, tetrakis- and pentakisphosphate) in relation to the rate of phytate synthesis during seed development in common bean (Phaseolus vulgaris)." J Plant Physiol 162(1);1-9. PMID: 15700415

Efanov97: Efanov AM, Zaitsev SV, Berggren PO (1997). "Inositol hexakisphosphate stimulates non-Ca2+-mediated and primes Ca2+-mediated exocytosis of insulin by activation of protein kinase C." Proc Natl Acad Sci U S A 94(9);4435-9. PMID: 9114007

French91: French PJ, Bunce CM, Stephens LR, Lord JM, McConnell FM, Brown G, Creba JA, Michell RH (1991). "Changes in the levels of inositol lipids and phosphates during the differentiation of HL60 promyelocytic cells towards neutrophils or monocytes." Proc Biol Sci 245(1314);193-201. PMID: 1684044

Fridy07: 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(42);30754-62. PMID: 17690096

Ives00: Ives EB, Nichols J, Wente SR, York JD (2000). "Biochemical and functional characterization of inositol 1,3,4,5, 6-pentakisphosphate 2-kinases." J Biol Chem 275(47);36575-83. PMID: 10960485

Larsson97: Larsson O, Barker CJ, Sjoholm A, Carlqvist H, Michell RH, Bertorello A, Nilsson T, Honkanen RE, Mayr GW, Zwiller J, Berggren PO (1997). "Inhibition of phosphatases and increased Ca2+ channel activity by inositol hexakisphosphate." Science 278(5337);471-4. PMID: 9334307

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Morrison02: Morrison BH, Bauer JA, Hu J, Grane RW, Ozdemir AM, Chawla-Sarkar M, Gong B, Almasan A, Kalvakolanu DV, Lindner DJ (2002). "Inositol hexakisphosphate kinase 2 sensitizes ovarian carcinoma cells to multiple cancer therapeutics." Oncogene 21(12);1882-9. PMID: 11896621

Nagase96: Nagase T, Seki N, Ishikawa K, Ohira M, Kawarabayasi Y, Ohara O, Tanaka A, Kotani H, Miyajima N, Nomura N (1996). "Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain." DNA Res 3(5);321-9, 341-54. PMID: 9039502

Nalaskowski02: Nalaskowski MM, Deschermeier C, Fanick W, Mayr GW (2002). "The human homologue of yeast ArgRIII protein is an inositol phosphate multikinase with predominantly nuclear localization." Biochem J 366(Pt 2);549-56. PMID: 12027805

Norbis97: Norbis F, Boll M, Stange G, Markovich D, Verrey F, Biber J, Murer H (1997). "Identification of a cDNA/protein leading to an increased Pi-uptake in Xenopus laevis oocytes." J Membr Biol 156(1);19-24. PMID: 9070460

Norris95: Norris FA, Ungewickell E, Majerus PW (1995). "Inositol hexakisphosphate binds to clathrin assembly protein 3 (AP-3/AP180) and inhibits clathrin cage assembly in vitro." J Biol Chem 270(1);214-7. PMID: 7814377

Phillippy94: Phillippy BQ, Ullah AH, Ehrlich KC (1994). "Purification and some properties of inositol 1,3,4,5,6-Pentakisphosphate 2-kinase from immature soybean seeds." J Biol Chem 269(45);28393-9. PMID: 7961779

Safrany98: Safrany ST, Caffrey JJ, Yang X, Bembenek ME, Moyer MB, Burkhart WA, Shears SB (1998). "A novel context for the 'MutT' module, a guardian of cell integrity, in a diphosphoinositol polyphosphate phosphohydrolase." EMBO J 17(22);6599-607. PMID: 9822604

Saiardi00: Saiardi A, Caffrey JJ, Snyder SH, Shears SB (2000). "Inositol polyphosphate multikinase (ArgRIII) determines nuclear mRNA export in Saccharomyces cerevisiae." FEBS Lett 468(1);28-32. PMID: 10683435

Schwanitz75: Schwanitz G, Reither M, Grosse G, Hagele C, Grosse K-P , Gutfried U (1975). "Partial monosomy 13 as the result of a balanced translocation 3/13 pat." Humangenetik 28(2);93-6. PMID: 1150275

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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