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MetaCyc Pathway: superpathway of inositol phosphate compounds
Traceable author statement to experimental support

Pathway diagram: superpathway of inositol phosphate compounds

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

Superclasses: BiosynthesisFatty Acid and Lipid BiosynthesisPhospholipid Biosynthesis
BiosynthesisSecondary Metabolites BiosynthesisSugar Derivatives BiosynthesisCyclitols Biosynthesis

Some taxa known to possess this pathway include : Saccharomyces cerevisiae

Expected Taxonomic Range: Eukaryota

The phosphorylated inositol compounds described in this superpathway can be divided into two major groups - the phospholipids phosphatidyl inositols, and the cyclitols inositol phosphates.

The most prominent stereomer of inositol in nature is myo-inositol. The inositol molecule has six hydroxyl groups, and each of these can be replaced by a single or double (pyro) phosphate group, resulting in a very large number of different forms of phosphorylated inositols.

Phosphatidyl-inositol phosphates

myo-inositol can combine with a CDP-diacylglycerol to form the glycerophospholipid an L-1-phosphatidyl-inositol, which serves as a a minor component in the cytosolic side of eukaryotic cell membranes. The most common fatty acids of phosphatidyl-inositol are stearate in the SN1 position and arachidonate in the SN2 position. When the inositol within the phospholipid is phosphorylated, the resulting phosphatidylinositol phosphate is called a phosphoinositide. Phosphoinositides can be phosphorylated at any of the 3', 4', or 5' positions on the inositol headgroup, generating a set of seven unique stereoisomers that have specific biological functions (see 3-phosphoinositide biosynthesis).

The phosphoinositides are membrane-bound lipids that function as structural components of membranes, as well as regulators of many cellular processes in eukaryotes, including vesicle-mediated membrane trafficking, cell wall integrity, and actin cytoskeleton organization. Different forms of phosphoinositides are associated with different membranes.

Phosphatidylinositol 4-phosphate is the major form in the Golgi apparatus, where it plays a role in the vesicular trafficking of secretory proteins from the Golgi to the plasma membrane.

Phosphatidylinositol 4,5-bisphosphate is the major form found at the plasma membrane and is involved in the regulation of actin cytoskeleton organization, as well as cell wall integrity, and heat shock response pathways.

Phosphatidylinositol 3-phosphate is found predominantly at endosomal membranes and in multivesicular bodies (MVB), where it plays a role in endosomal and vacuolar membrane trafficking.

Phosphatidylinositol 3,5-bisphosphate is found on vacuolar membranes where it plays an important role in the MVB sorting pathway.

Phosphatidyl-1D-myo-inositol 3,4-bisphosphate is used in as a secondary messenger, involved in the regulation of cellular events including growth, differentiation, vesicular sorting, glucose transport and platelet aggregation [Zhang98a, Shearn01].

Inositol phosphates

The phospholipid phosphatidylinositol 4,5-bisphosphate can be hydrolyzed by the phospholipase C enzymes to form the extremely important secondary messanger compound D-myo-inositol (1,4,5)-trisphosphate (see D-myo-inositol (1,4,5)-trisphosphate biosynthesis). In addition to its role as a second messenger, D-myo-inositol (1,4,5)-trisphosphate is the starting point of several complex pathways that produce many different forms of phosphorylated inositols.

D-myo-inositol (1,4,5)-trisphosphate can be phosphorylated, either in a direct route (see 1D-myo-inositol hexakisphosphate biosynthesis I (from Ins(1,4,5)P3)) or via D-myo-inositol (1,3,4)-trisphosphate (see 1D-myo-inositol hexakisphosphate biosynthesis II (mammalian)), to the fully phosphorylated form phytate, also known as phytate. One of the intermediates of this pathway, D-myo-inositol 1,3,4,5,6-pentakisphosphate, is used to synthesize two other important secondary messengers - D-myo-inositol (1,4,5,6)-tetrakisphosphate (see D-myo-inositol (1,4,5,6)-tetrakisphosphate biosynthesis) and D-myo-inositol (3,4,5,6)-tetrakisphosphate (see D-myo-inositol (3,4,5,6)-tetrakisphosphate biosynthesis).

Phosphorylation does not end at phytate - this molecule is phosphorylated further by modification of one or more of the phosphates to pyrophosphates (see inositol pyrophosphates biosynthesis).

Even though not part of this pathway, the timely degration of these compounds is also a crucial part of their metabolism. More about it is available in 3-phosphoinositide degradation.

Subpathways: inositol pyrophosphates biosynthesis, D-myo-inositol-5-phosphate metabolism, 3-phosphoinositide biosynthesis, D-myo-inositol (1,4,5,6)-tetrakisphosphate biosynthesis, D-myo-inositol (3,4,5,6)-tetrakisphosphate biosynthesis, 1D-myo-inositol hexakisphosphate biosynthesis II (mammalian)

Created 02-Nov-2009 by Caspi R, SRI International


Ivetac05: Ivetac I, Munday AD, Kisseleva MV, Zhang XM, Luff S, Tiganis T, Whisstock JC, Rowe T, Majerus PW, Mitchell CA (2005). "The type Ialpha inositol polyphosphate 4-phosphatase generates and terminates phosphoinositide 3-kinase signals on endosomes and the plasma membrane." Mol Biol Cell 16(5);2218-33. PMID: 15716355

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

Shearn01: Shearn CT, Walker J, Norris FA (2001). "Identification of a novel spliceoform of inositol polyphosphate 4-phosphatase type Ialpha expressed in human platelets: structure of human inositol polyphosphate 4-phosphatase type I gene." Biochem Biophys Res Commun 286(1);119-25. PMID: 11485317

Strahl07: Strahl T, Thorner J (2007). "Synthesis and function of membrane phosphoinositides in budding yeast, Saccharomyces cerevisiae." Biochim Biophys Acta 1771(3);353-404. PMID: 17382260

Zhang07a: Zhang Y, Zolov SN, Chow CY, Slutsky SG, Richardson SC, Piper RC, Yang B, Nau JJ, Westrick RJ, Morrison SJ, Meisler MH, Weisman LS (2007). "Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice." Proc Natl Acad Sci U S A 104(44);17518-23. PMID: 17956977

Zhang98a: Zhang X, Majerus PW (1998). "Phosphatidylinositol signalling reactions." Semin Cell Dev Biol 9(2);153-60. PMID: 9599410

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

Antonsson94: Antonsson BE (1994). "Purification and characterization of phosphatidylinositol synthase from human placenta." Biochem J 297 ( Pt 3);517-22. PMID: 8110188

Arcaro98: Arcaro A, Volinia S, Zvelebil MJ, Stein R, Watton SJ, Layton MJ, Gout I, Ahmadi K, Downward J, Waterfield MD (1998). "Human phosphoinositide 3-kinase C2beta, the role of calcium and the C2 domain in enzyme activity." J Biol Chem 273(49);33082-90. PMID: 9830063

Barker92: Barker CJ, Wong NS, Maccallum SM, Hunt PA, Michell RH, Kirk CJ (1992). "The interrelationships of the inositol phosphates formed in vasopressin-stimulated WRK-1 rat mammary tumour cells." Biochem J 286 ( Pt 2);469-74. PMID: 1530578

Barylko01: Barylko B, Gerber SH, Binns DD, Grichine N, Khvotchev M, Sudhof TC, Albanesi JP (2001). "A novel family of phosphatidylinositol 4-kinases conserved from yeast to humans." J Biol Chem 276(11);7705-8. PMID: 11244087

Bazenet90: Bazenet CE, Ruano AR, Brockman JL, Anderson RA (1990). "The human erythrocyte contains two forms of phosphatidylinositol-4-phosphate 5-kinase which are differentially active toward membranes." J Biol Chem 265(29);18012-22. PMID: 2170402

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

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

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

Boldyreff08: Boldyreff B, Rasmussen TL, Jensen HH, Cloutier A, Beaudet L, Roby P, Issinger OG (2008). "Expression and purification of PI3 kinase alpha and development of an ATP depletion and an alphascreen PI3 kinase activity assay." J Biomol Screen 13(10);1035-40. PMID: 19036708

Bonangelino02: Bonangelino CJ, Nau JJ, Duex JE, Brinkman M, Wurmser AE, Gary JD, Emr SD, Weisman LS (2002). "Osmotic stress-induced increase of phosphatidylinositol 3,5-bisphosphate requires Vac14p, an activator of the lipid kinase Fab1p." J Cell Biol 156(6);1015-28. PMID: 11889142

Botelho08: Botelho RJ, Efe JA, Teis D, Emr SD (2008). "Assembly of a Fab1 phosphoinositide kinase signaling complex requires the Fig4 phosphoinositide phosphatase." Mol Biol Cell 19(10);4273-86. PMID: 18653468

Brock03: Brock C, Schaefer M, Reusch HP, Czupalla C, Michalke M, Spicher K, Schultz G, Nurnberg B (2003). "Roles of G beta gamma in membrane recruitment and activation of p110 gamma/p101 phosphoinositide 3-kinase gamma." J Cell Biol 160(1);89-99. PMID: 12507995

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

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

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

Carricaburu03: Carricaburu V, Lamia KA, Lo E, Favereaux L, Payrastre B, Cantley LC, Rameh LE (2003). "The phosphatidylinositol (PI)-5-phosphate 4-kinase type II enzyme controls insulin signaling by regulating PI-3,4,5-trisphosphate degradation." Proc Natl Acad Sci U S A 100(17);9867-72. PMID: 12897244

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

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

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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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