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MetaCyc Pathway: 3-phosphoinositide biosynthesis
Traceable author statement to experimental support

Pathway diagram: 3-phosphoinositide biosynthesis

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

Synonyms: phosphatidylinositol-3,4-bisphosphate biosynthesis, phosphatidylinositol 3-phosphate biosynthesis, phosphatidylinositol-3,4,5-triphosphate biosynthesis

Superclasses: BiosynthesisFatty Acid and Lipid BiosynthesisPhospholipid Biosynthesis

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

Expected Taxonomic Range: Eukaryota

Phosphoinositides play a key role in signal transduction in the eukaryotic cell, transmitting signals from the cell surface to modulate intracellular processes. One well known phosphoinositide pathway produces the secondary messengers D-myo-inositol (1,4,5)-trisphosphate and diacylglycerol and is described in D-myo-inositol (1,4,5)-trisphosphate biosynthesis.

The 3-phosphoinositide pathway described here is another one of the major pathways of intracellular signal transduction. At the center of this pathway are the phosphatidylinositol 3-kinases (PI 3-kinases), enzymes that produce the monophosphate phosphatidylinositol 3-phosphate, the bisphosphate phosphatidylinositol 3,4-bisphosphate and the trisphosphate phosphatidylinositol 3,4,5-trisphosphate, all important compounds in signaling cascades that influences a wide variety of cellular functions.

The 3-phosphoinositide pathway has been implicated in growth factor-dependent mitogenesis, membrane ruffling and glucose uptake, cell proliferation, oncogenic transformation, cell survival, cell migration, and intracellular protein trafficking. [Kapeller94]. Some of the products of the PI 3-kinases, namely phosphatidylinositol 3,4-bisphosphate and the trisphosphate phosphatidylinositol 3,4,5-trisphosphate, are almost absent in quiescent cells but are produced rapidly upon stimulation by a variety of factors, suggesting a likely function as second messengers. In addition, these compounds do not seem to be substrates for phospholipases C [Serunian89], and it has been proposed that they may act via the activation of certain protein kinases such as Akt/RAC/PKB and certain protein kinase C isoforms [Liscovitch94, Toker94].

The enzymes responsible for the generation of 3' phosphoinositides, phosphatidylinositol 3-kinases, have been assigned to three classes based on structural similarity, substrate specificity, and probable mechanism of activation [Domin97].

Class I is composed of heterodimeric enzymes, each containing one catalytic subunit, encoded by PIK3CA, PIK3CB, PIK3CG or PIK3CD, and one regulatory subunit, encoded by PIK3R1, PIK3R2, PIK3R3, PIK3R5 or PIK3R6. Even though all class I enzymes can phosphorylate in vitro phosphatidylinositol, a 1-phosphatidyl-1D-myo-inositol 4-phosphate and a 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate, only the later is beleived to be the in vivo substrate ( EC

Class II enzymes are monomeric proteins that are distinguished by a carboxy-terminal C2 (CalB) Ca2+-binding domain [Rizo98], and are encoded by PIK3C2A, PIK3C2B and PIK3C2G. They accept several types of substrates, and are the only mammalian enzyme thought to catalyze EC

Class III enzymes are heterodimeric, composed of a catalytic subunit ( PIK3C3) and a regulatory subunit ( PIK3R4). These enzymes, which are homologs of the yeast Vps34p protein, can only phosphorylate an L-1-phosphatidyl-inositol ( EC

Superpathways: superpathway of inositol phosphate compounds

Created 09-Oct-2009 by Caspi R, SRI International


Domin97: Domin J, Waterfield MD (1997). "Using structure to define the function of phosphoinositide 3-kinase family members." FEBS Lett 410(1);91-5. PMID: 9247130

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

Kapeller94: Kapeller R, Cantley LC (1994). "Phosphatidylinositol 3-kinase." Bioessays 16(8);565-76. PMID: 8086005

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

Liscovitch94: Liscovitch M, Cantley LC (1994). "Lipid second messengers." Cell 77(3);329-34. PMID: 8181054

Rizo98: Rizo J, Sudhof TC (1998). "C2-domains, structure and function of a universal Ca2+-binding domain." J Biol Chem 273(26);15879-82. PMID: 9632630

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

Serunian89: Serunian LA, Haber MT, Fukui T, Kim JW, Rhee SG, Lowenstein JM, Cantley LC (1989). "Polyphosphoinositides produced by phosphatidylinositol 3-kinase are poor substrates for phospholipases C from rat liver and bovine brain." J Biol Chem 264(30);17809-15. PMID: 2553693

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

Toker94: Toker A, Meyer M, Reddy KK, Falck JR, Aneja R, Aneja S, Parra A, Burns DJ, Ballas LM, Cantley LC (1994). "Activation of protein kinase C family members by the novel polyphosphoinositides PtdIns-3,4-P2 and PtdIns-3,4,5-P3." J Biol Chem 269(51);32358-67. PMID: 7798235

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

Antonsson97: Antonsson B (1997). "Phosphatidylinositol synthase from mammalian tissues." Biochim Biophys Acta 1348(1-2);179-86. PMID: 9370331

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

Balla01: Balla T (2001). "Pharmacology of phosphoinositides, regulators of multiple cellular functions." Curr Pharm Des 7(6);475-507. PMID: 11281854

Balla02: Balla A, Tuymetova G, Barshishat M, Geiszt M, Balla T (2002). "Characterization of type II phosphatidylinositol 4-kinase isoforms reveals association of the enzymes with endosomal vesicular compartments." J Biol Chem 277(22);20041-50. PMID: 11923287

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

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

Brown97: Brown RA, Ho LK, Weber-Hall SJ, Shipley JM, Fry MJ (1997). "Identification and cDNA cloning of a novel mammalian C2 domain-containing phosphoinositide 3-kinase, HsC2-PI3K." Biochem Biophys Res Commun 233(2);537-44. PMID: 9144573

Brown99: Brown RA, Domin J, Arcaro A, Waterfield MD, Shepherd PR (1999). "Insulin activates the alpha isoform of class II phosphoinositide 3-kinase." J Biol Chem 274(21);14529-32. PMID: 10329640

Cabezas06: Cabezas A, Pattni K, Stenmark H (2006). "Cloning and subcellular localization of a human phosphatidylinositol 3-phosphate 5-kinase, PIKfyve/Fab1." Gene 371(1);34-41. PMID: 16448788

Caldwell01: Caldwell GM, Eddy RL, Day CD, Haley LH, Cooper PR, Sait SS, Hejtmancik F, Smith RJ, Morton CC, Higgins MJ, Shows TB (2001). "Mapping of genes and transcribed sequences in a gene rich 400-kb region on human chromosome 11p15.1-->p14." Cytogenet Cell Genet 92(1-2);103-7. PMID: 11306805

Cannizzaro91: Cannizzaro LA, Skolnik EY, Margolis B, Croce CM, Schlesinger J, Huebner K (1991). "The human gene encoding phosphatidylinositol-3 kinase associated p85 alpha is at chromosome region 5q12-13." Cancer Res 51(14);3818-20. PMID: 1648445

Carpenter90: Carpenter CL, Duckworth BC, Auger KR, Cohen B, Schaffhausen BS, Cantley LC (1990). "Purification and characterization of phosphoinositide 3-kinase from rat liver." J Biol Chem 265(32);19704-11. PMID: 2174051

Carpenter93: Carpenter CL, Auger KR, Duckworth BC, Hou WM, Schaffhausen B, Cantley LC (1993). "A tightly associated serine/threonine protein kinase regulates phosphoinositide 3-kinase activity." Mol Cell Biol 13(3);1657-65. PMID: 8382773

Carson08: Carson JD, Van Aller G, Lehr R, Sinnamon RH, Kirkpatrick RB, Auger KR, Dhanak D, Copeland RA, Gontarek RR, Tummino PJ, Luo L (2008). "Effects of oncogenic p110alpha subunit mutations on the lipid kinase activity of phosphoinositide 3-kinase." Biochem J 409(2);519-24. PMID: 17877460

Carvajal95: Carvajal JJ, Pook MA, Doudney K, Hillermann R, Wilkes D, al-Mahdawi S, Williamson R, Chamberlain S (1995). "Friedreich's ataxia: a defect in signal transduction?." Hum Mol Genet 4(8);1411-9. PMID: 7581382

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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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