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:||Biosynthesis → Fatty Acid and Lipid Biosynthesis → Phospholipid Biosynthesis|
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 18.104.22.168).
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 22.214.171.124.
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 126.96.36.199).
Superpathways: superpathway of inositol phosphate compounds
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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
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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
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
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
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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
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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
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
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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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