MetaCyc Pathway: D-myo-inositol (1,4,5,6)-tetrakisphosphate biosynthesis
Inferred from experiment

Pathway diagram: D-myo-inositol (1,4,5,6)-tetrakisphosphate biosynthesis

This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Superclasses: BiosynthesisSecondary Metabolites BiosynthesisSugar Derivatives BiosynthesisCyclitols Biosynthesis

Some taxa known to possess this pathway include : Homo sapiens

Expected Taxonomic Range: Eukaryota

Like several other inositol phosphates, D-myo-inositol (1,4,5,6)-tetrakisphosphate is a second messenger molecule that plays a critical role in cellular signaling [BlumHeld01]. At micromolar concentrations it inhibits IGF-1-induced thymidine incorporation in human breast cancer cells and thus prevents the ability of these cells to grow [Razzini00]. It is also involved in nuclear processes since it is required for gene regulation and may control gene expression [Odom00].

D-myo-inositol 1,3,4,5,6-pentakisphosphate exists in most mammalian cells at micromolar concentrations, and is considered one of two major inositol phosphates in the cell (along with phytate). Unlike in yeast, where D-myo-inositol (1,4,5,6)-tetrakisphosphate is an intermediate in the biosynthesis of D-myo-inositol 1,3,4,5,6-pentakisphosphate and phytate, the human pathway proceeds via D-myo-inositol (1,3,4,6)-tetrakisphosphate, which is phosphorylated to D-myo-inositol 1,3,4,5,6-pentakisphosphate by inositol 1,3,4,6-tetrakisphosphate 5-kinase (see 1D-myo-inositol hexakisphosphate biosynthesis II (mammalian)) [Verbsky05]. That enzyme has a clear preference for D-myo-inositol (1,3,4,6)-tetrakisphosphate over D-myo-inositol (1,3,4,5)-tetrakisphosphate [Chang02].

Multiple biochemical evidence suggests that the major source for D-myo-inositol (1,3,4,5)-tetrakisphosphate in mammals is the dephosphorylation of D-myo-inositol 1,3,4,5,6-pentakisphosphate, catalyzed by multiple inositol polyphosphate phosphatase 1 [Oliver92, Craxton97]. Once formed, it can be deactivated by its conversion back to the petakisphosphate form by inositol 1,3,4,6-tetrakisphosphate 5-kinase, despite the lower affinity of this enzyme towards D-myo-inositol (1,3,4,5)-tetrakisphosphate [Chang06].

This pathway is manipulated by the pathogen Salmonella enterica. Upon infection, the bacterium introduces the virulence factor sopB into the gastrointestinal cell. SopB is an inositol phosphatase and catalyzes the dephosphorylation of D-myo-inositol 1,3,4,5,6-pentakisphosphate to D-myo-inositol (1,4,5,6)-tetrakisphosphate. This results in an increased chloride channel activity, contributing to diarrhea in the host, and potentially facilitates bacterial entry into the cells [Feng01, Eckmann97].

Superpathways: superpathway of inositol phosphate compounds

Created 22-Oct-2009 by Caspi R, SRI International


BlumHeld01: Blum-Held C, Bernard P, Schlewer G, Spiess B (2001). "myo-Inositol 1,4,5,6-tetrakisphosphate and myo-inositol 3,4,5,6-tetrakisphosphate, two second messengers that may act as pH-dependent molecular switches." J Am Chem Soc 123(14);3399-400. PMID: 11457089

Chang02: 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

Chang06: Chang SC, Majerus PW (2006). "Inositol polyphosphate multikinase regulates inositol 1,4,5,6-tetrakisphosphate." Biochem Biophys Res Commun 339(1);209-16. PMID: 16293229

Craxton97: Craxton A, Caffrey JJ, Burkhart W, Safrany ST, Shears SB (1997). "Molecular cloning and expression of a rat hepatic multiple inositol polyphosphate phosphatase." Biochem J 328 ( Pt 1);75-81. PMID: 9359836

Eckmann97: Eckmann L, Rudolf MT, Ptasznik A, Schultz C, Jiang T, Wolfson N, Tsien R, Fierer J, Shears SB, Kagnoff MF, Traynor-Kaplan AE (1997). "D-myo-Inositol 1,4,5,6-tetrakisphosphate produced in human intestinal epithelial cells in response to Salmonella invasion inhibits phosphoinositide 3-kinase signaling pathways." Proc Natl Acad Sci U S A 94(26);14456-60. PMID: 9405634

Feng01: Feng Y, Wente SR, Majerus PW (2001). "Overexpression of the inositol phosphatase SopB in human 293 cells stimulates cellular chloride influx and inhibits nuclear mRNA export." Proc Natl Acad Sci U S A 98(3);875-9. PMID: 11158563

Odom00: Odom AR, Stahlberg A, Wente SR, York JD (2000). "A role for nuclear inositol 1,4,5-trisphosphate kinase in transcriptional control." Science 287(5460);2026-9. PMID: 10720331

Oliver92: Oliver KG, Putney JW, Obie JF, Shears SB (1992). "The interconversion of inositol 1,3,4,5,6-pentakisphosphate and inositol tetrakisphosphates in AR4-2J cells." J Biol Chem 267(30);21528-34. PMID: 1328236

Razzini00: Razzini G, Berrie CP, Vignati S, Broggini M, Mascetta G, Brancaccio A, Falasca M (2000). "Novel functional PI 3-kinase antagonists inhibit cell growth and tumorigenicity in human cancer cell lines." FASEB J 14(9);1179-87. PMID: 10834940

Verbsky05: Verbsky JW, Chang SC, Wilson MP, Mochizuki Y, Majerus PW (2005). "The pathway for the production of inositol hexakisphosphate in human cells." J Biol Chem 280(3);1911-20. PMID: 15531582

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

Caffrey99: Caffrey JJ, Hidaka K, Matsuda M, Hirata M, Shears SB (1999). "The human and rat forms of multiple inositol polyphosphate phosphatase: functional homology with a histidine acid phosphatase up-regulated during endochondral ossification." FEBS Lett 442(1);99-104. PMID: 9923613

Chi99: Chi H, Tiller GE, Dasouki MJ, Romano PR, Wang J, O'keefe RJ, Puzas JE, Rosier RN, Reynolds PR (1999). "Multiple inositol polyphosphate phosphatase: evolution as a distinct group within the histidine phosphatase family and chromosomal localization of the human and mouse genes to chromosomes 10q23 and 19." Genomics 56(3);324-36. PMID: 10087200

Cho08: Cho J, King JS, Qian X, Harwood AJ, Shears SB (2008). "Dephosphorylation of 2,3-bisphosphoglycerate by MIPP expands the regulatory capacity of the Rapoport-Luebering glycolytic shunt." Proc Natl Acad Sci U S A 105(16);5998-6003. PMID: 18413611

Craxton95: Craxton A, Ali N, Shears SB (1995). "Comparison of the activities of a multiple inositol polyphosphate phosphatase obtained from several sources: a search for heterogeneity in this enzyme." Biochem J 305 ( Pt 2);491-8. PMID: 7832765

Gimm01: Gimm O, Chi H, Dahia PL, Perren A, Hinze R, Komminoth P, Dralle H, Reynolds PR, Eng C (2001). "Somatic mutation and germline variants of MINPP1, a phosphatase gene located in proximity to PTEN on 10q23.3, in follicular thyroid carcinomas." J Clin Endocrinol Metab 86(4);1801-5. PMID: 11297621

Ho02: Ho, M. W.K., Yang, X., Carew, M.A., Zhang, T, Hua, L., Kwon, Y., Chung, S., Adelt, S., Vogel, G., Riley, A.M., Potter, B.V.L., Shears, S.B. (2002). "Regulation of Ins(3,4,5,6)P4 Signaling by a Reversible Kinase/Phosphatase." Curr. Biol. 12(6): 477-482.

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

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

Reynolds96: Reynolds SD, Johnston C, Leboy PS, O'Keefe RJ, Puzas JE, Rosier RN, Reynolds PR (1996). "Identification and characterization of a unique chondrocyte gene involved in transition to hypertrophy." Exp Cell Res 226(1);197-207. PMID: 8660956

Riley06a: Riley AM, Deleu S, Qian X, Mitchell J, Chung SK, Adelt S, Vogel G, Potter BV, Shears SB (2006). "On the contribution of stereochemistry to human ITPK1 specificity: Ins(1,4,5,6)P4 is not a physiologic substrate." FEBS Lett 580(1);324-30. PMID: 16376887

Romano98: Romano PR, Wang J, O'Keefe RJ, Puzas JE, Rosier RN, Reynolds PR (1998). "HiPER1, a phosphatase of the endoplasmic reticulum with a role in chondrocyte maturation." J Cell Sci 111 ( Pt 6);803-13. PMID: 9472008

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

Saiardi01: 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

Shears89: Shears SB (1989). "The pathway of myo-inositol 1,3,4-trisphosphate phosphorylation in liver. Identification of myo-inositol 1,3,4-trisphosphate 6-kinase, myo-inositol 1,3,4-trisphosphate 5-kinase, and myo-inositol 1,3,4,6-tetrakisphosphate 5-kinase." J Biol Chem 264(33);19879-86. PMID: 2584198

Stephens90: Stephens LR, Irvine RF (1990). "Stepwise phosphorylation of myo-inositol leading to myo-inositol hexakisphosphate in Dictyostelium." Nature 346(6284);580-3. PMID: 2198472

StevensonPaulik02: Stevenson-Paulik J, Odom AR, York JD (2002). "Molecular and biochemical characterization of two plant inositol polyphosphate 6-/3-/5-kinases." J Biol Chem 277(45);42711-8. PMID: 12226109

StevensonPaulik05: Stevenson-Paulik J, Bastidas RJ, Chiou ST, Frye RA, York JD (2005). "Generation of phytate-free seeds in Arabidopsis through disruption of inositol polyphosphate kinases." Proc Natl Acad Sci U S A 102(35);12612-7. PMID: 16107538

Wilson96: Wilson MP, Majerus PW (1996). "Isolation of inositol 1,3,4-trisphosphate 5/6-kinase, cDNA cloning and expression of the recombinant enzyme." J Biol Chem 271(20);11904-10. PMID: 8662638

Wilson97: Wilson MP, Majerus PW (1997). "Characterization of a cDNA encoding Arabidopsis thaliana inositol 1,3,4-trisphosphate 5/6-kinase." Biochem Biophys Res Commun 232(3);678-81. PMID: 9126335

Yang00: Yang X, Shears SB (2000). "Multitasking in signal transduction by a promiscuous human Ins(3,4,5,6)P(4) 1-kinase/Ins(1,3,4)P(3) 5/6-kinase." Biochem J 351 Pt 3;551-5. PMID: 11042108

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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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