MetaCyc Pathway: superpathway of D-myo-inositol (1,4,5)-trisphosphate metabolism
Inferred from experiment

Enzyme View:

Pathway diagram: superpathway of D-myo-inositol (1,4,5)-trisphosphate metabolism

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, Saccharomyces cerevisiae

Expected Taxonomic Range: Eukaryota

D-myo-inositol (1,4,5)-trisphosphate is a secondary messenger molecule used in signal transduction and lipid signaling in eukaryotic cells. It mediates the biological response of a large number of hormones and neurotransmitters in target cells by regulating calcium release from intracellular stores. D-myo-inositol (1,4,5)-trisphosphate is synthesized by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid that is located in the plasma membrane, by the action of phospholipase C, as described in D-myo-inositol (1,4,5)-trisphosphate biosynthesis.

Once formed, the levels of D-myo-inositol (1,4,5)-trisphosphate are tightly regulated by two mechanisms.

In the first mechanism the compound is dephosphorylated to D-myo-inositol (1,4)-bisphosphate [Downes82, Storey84], initiating a pathway that recycles the inositol moiety to the plasma membrane as phosphatidylinositols.

In the second mechanism, it is phosphorylated by inositol 1,4,5-trisphosphate 3-kinase to D-myo-inositol (1,3,4,5)-tetrakisphosphate. This compound has been suggested to have roles in controlling calcium homeostasis, transferring calcium between intracellular stores, and/or regulating calcium entry across the plasma membrane [Irvine91]. It may also play a role in regulating cross-talk between the calcium and other signaling pathways. A D-myo-inositol (1,3,4,5)-tetrakisphosphate-binding protein has been identified that can stimulate the GTPase activity of the ras and rap small GTP binding proteins [Cullen95, Soriano97].

D-myo-inositol (1,3,4,5)-tetrakisphosphate can be cleaved to D-myo-inositol (1,3,4)-trisphosphate [Irvine86], or it could be phosphorylated further to D-myo-inositol 1,3,4,5,6-pentakisphosphate and eventually I phytate [Berridge89, Shears89a], as described in 1D-myo-inositol hexakisphosphate biosynthesis I (from Ins(1,4,5)P3).

D-myo-inositol (1,3,4)-trisphosphate links the degree and duration of receptor-dependent phospholipase C activation to the generation of D-myo-inositol (3,4,5,6)-tetrakisphosphate, a cellular signal that regulates the ionic conductance of Cl-channels [Xie98, Yang99, Shears98].

Subpathways: D-myo-inositol (1,4,5)-trisphosphate degradation, D-myo-inositol (1,3,4)-trisphosphate biosynthesis

Created 19-Oct-2009 by Caspi R, SRI International


Berridge89: Berridge MJ, Irvine RF (1989). "Inositol phosphates and cell signalling." Nature 341(6239);197-205. PMID: 2550825

Cullen95: Cullen PJ, Hsuan JJ, Truong O, Letcher AJ, Jackson TR, Dawson AP, Irvine RF (1995). "Identification of a specific Ins(1,3,4,5)P4-binding protein as a member of the GAP1 family." Nature 376(6540);527-30. PMID: 7637787

Downes82: Downes CP, Mussat MC, Michell RH (1982). "The inositol trisphosphate phosphomonoesterase of the human erythrocyte membrane." Biochem J 203(1);169-77. PMID: 6285891

Irvine86: Irvine RF, Letcher AJ, Heslop JP, Berridge MJ (1986). "The inositol tris/tetrakisphosphate pathway - demonstration of Ins(1,4,5)P3 3-kinase activity in animal tissues." Nature 320(6063);631-4. PMID: 3010126

Irvine91: Irvine RF (1991). "Inositol tetrakisphosphate as a second messenger: confusions, contradictions, and a potential resolution." Bioessays 13(8);419-27. PMID: 1659392

Lecompte08: Lecompte O, Poch O, Laporte J (2008). "PtdIns5P regulation through evolution: roles in membrane trafficking?." Trends Biochem Sci 33(10);453-60. PMID: 18774718

Rohde02: Rohde G, Wenzel D, Haucke V (2002). "A phosphatidylinositol (4,5)-bisphosphate binding site within mu2-adaptin regulates clathrin-mediated endocytosis." J Cell Biol 158(2);209-14. PMID: 12119359

Shears89a: Shears SB (1989). "Metabolism of the inositol phosphates produced upon receptor activation." Biochem J 260(2);313-24. PMID: 2548474

Shears98: Shears SB (1998). "The versatility of inositol phosphates as cellular signals." Biochim Biophys Acta 1436(1-2);49-67. PMID: 9838040

Soriano97: Soriano S, Banting G (1997). "Possible roles of inositol 1,4,5-trisphosphate 3-kinase B in calcium homeostasis." FEBS Lett 403(1);1-4. PMID: 9038348

Storey84: Storey DJ, Shears SB, Kirk CJ, Michell RH (1984). "Stepwise enzymatic dephosphorylation of inositol 1,4,5-trisphosphate to inositol in liver." Nature 312(5992);374-6. PMID: 6095097

Xie98: Xie W, Solomons KR, Freeman S, Kaetzel MA, Bruzik KS, Nelson DJ, Shears SB (1998). "Regulation of Ca2+-dependent Cl- conductance in a human colonic epithelial cell line (T84): cross-talk between Ins(3,4,5,6)P4 and protein phosphatases." J Physiol 510 ( Pt 3);661-73. PMID: 9660883

Yang99: Yang X, Rudolf M, Carew MA, Yoshida M, Nerreter V, Riley AM, Chung SK, Bruzik KS, Potter BV, Schultz C, Shears SB (1999). "Inositol 1,3,4-trisphosphate acts in vivo as a specific regulator of cellular signaling by inositol 3,4,5,6-tetrakisphosphate." J Biol Chem 274(27);18973-80. PMID: 10383396

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

Arai07: Arai R, Ito K, Ohnishi T, Ohba H, Akasaka R, Bessho Y, Hanawa-Suetsugu K, Yoshikawa T, Shirouzu M, Yokoyama S (2007). "Crystal structure of human myo-inositol monophosphatase 2, the product of the putative susceptibility gene for bipolar disorder, schizophrenia, and febrile seizures." Proteins 67(3);732-42. PMID: 17340635

Attree92: Attree O, Olivos IM, Okabe I, Bailey LC, Nelson DL, Lewis RA, McInnes RR, Nussbaum RL (1992). "The Lowe's oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5-phosphatase." Nature 358(6383);239-42. PMID: 1321346

Berdy01: Berdy SE, Kudla J, Gruissem W, Gillaspy GE (2001). "Molecular characterization of At5PTase1, an inositol phosphatase capable of terminating inositol trisphosphate signaling." Plant Physiol 126(2);801-10. PMID: 11402208

Bone92: Bone R, Springer JP, Atack JR (1992). "Structure of inositol monophosphatase, the putative target of lithium therapy." Proc Natl Acad Sci U S A 89(21);10031-5. PMID: 1332026

Bone94: Bone R, Frank L, Springer JP, Atack JR (1994). "Structural studies of metal binding by inositol monophosphatase: evidence for two-metal ion catalysis." Biochemistry 33(32);9468-76. PMID: 8068621

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

Chang02b: 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

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

Cho08a: 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

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

Cremona00: Cremona O, Nimmakayalu M, Haffner C, Bray-Ward P, Ward DC, De Camilli P (2000). "Assignment of SYNJ1 to human chromosome 21q22.2 and Synj12 to the murine homologous region on chromosome 16C3-4 by in situ hybridization." Cytogenet Cell Genet 88(1-2);89-90. PMID: 10773674

Cullen94: Cullen PJ, Patel Y, Kakkar VV, Irvine RF, Authi KS (1994). "Specific binding sites for inositol 1,3,4,5-tetrakisphosphate are located predominantly in the plasma membranes of human platelets." Biochem J 298 Pt 3;739-42. PMID: 8141791

Cullen95a: Cullen PJ, Chung SK, Chang YT, Dawson AP, Irvine RF (1995). "Specificity of the purified inositol (1,3,4,5) tetrakisphosphate-binding protein from porcine platelets." FEBS Lett 358(3);240-2. PMID: 7843408

Cullen97: Cullen PJ, Loomis-Husselbee J, Dawson AP, Irvine RF (1997). "Inositol 1,3,4,5-tetrakisphosphate and Ca2+ homoeostasis: the role of GAP1IP4BP." Biochem Soc Trans 25(3);991-6. PMID: 9388588

Damen96: Damen JE, Liu L, Rosten P, Humphries RK, Jefferson AB, Majerus PW, Krystal G (1996). "The 145-kDa protein induced to associate with Shc by multiple cytokines is an inositol tetraphosphate and phosphatidylinositol 3,4,5-triphosphate 5-phosphatase." Proc Natl Acad Sci U S A 93(4);1689-93. PMID: 8643691

De94: De Smedt F, Verjans B, Mailleux P, Erneux C (1994). "Cloning and expression of human brain type I inositol 1,4,5-trisphosphate 5-phosphatase. High levels of mRNA in cerebellar Purkinje cells." FEBS Lett 347(1);69-72. PMID: 8013665

De96a: De Smedt F, Boom A, Pesesse X, Schiffmann SN, Erneux C (1996). "Post-translational modification of human brain type I inositol-1,4,5-trisphosphate 5-phosphatase by farnesylation." J Biol Chem 271(17);10419-24. PMID: 8626616

Dewaste00: 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 Pt 2;343-51. PMID: 11085927

Dewaste02: Dewaste V, Roymans D, Moreau C, Erneux C (2002). "Cloning and expression of a full-length cDNA encoding human inositol 1,4,5-trisphosphate 3-kinase B." Biochem Biophys Res Commun 291(2);400-5. PMID: 11846419

Drayer96: Drayer AL, Pesesse X, De Smedt F, Woscholski R, Parker P, Erneux C (1996). "Cloning and expression of a human placenta inositol 1,3,4,5-tetrakisphosphate and phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase." Biochem Biophys Res Commun 225(1);243-9. PMID: 8769125

Showing only 20 references. To show more, press the button "Show all references".

Report Errors or Provide Feedback
Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by Pathway Tools version 20.0 (software by SRI International) on Fri May 6, 2016, BIOCYC13B.