Inositol phosphates (IPs) are molecules involves in signalling processes in eukaryotes. myo-Inositol consists of a six-carbon cyclic alcohol with an axial 2-hydroxy and five equatorial hydroxyls. Mono-, di-, and triphosphorylation of the inositol ring generates a wide variety of stereochemically distinct signalling entities. Inositol 1,4,5-trisphosphate (I(1,4,5)P3), is formed when the phosphoinositide phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) is hydrolysed by a phospholipase C isozyme. An array of inositol trisphosphate (IP3) and tetrakisphosphate (IP4) molecules are synthesised by the action of various kinases and phosphatases in the cytosol. These species then transport between the cytosol and the nucleus where they are acted on by inositol polyphosphate multikinase (IPMK), inositol-pentakisphosphate 2-kinase (IPPK), inositol hexakisphosphate kinase 1 (IP6K1) and 2 (IP6K2), to produce IP5, IP6, IP7, and IP8 molecules. Some of these nuclear produced IPs transport back to the cytosol where they are converted to an even wider variety of IPs, by kinases and phosphatases, including the di- and triphospho inositol phosphates aka pyrophosphates (Irvine & Schell 2001, Bunney & Katan 2010, Alcazar-Romain & Wente 2008, York 2006, Monserrate and York 2010).
View original pathway at Reactome.
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Dewaste V, Moreau C, De Smedt F, Bex F, De Smedt H, Wuytack F, Missiaen L, Erneux C.; ''The three isoenzymes of human inositol-1,4,5-trisphosphate 3-kinase show specific intracellular localization but comparable Ca2+ responses on transfection in COS-7 cells.''; PubMedEurope PMCScholia
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Alvarez RA, Ghalayini AJ, Xu P, Hardcastle A, Bhattacharya S, Rao PN, Pettenati MJ, Anderson RE, Baehr W.; ''cDNA sequence and gene locus of the human retinal phosphoinositide-specific phospholipase-C beta 4 (PLCB4).''; PubMedEurope PMCScholia
Maehama T, Dixon JE.; ''The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate.''; PubMedEurope PMCScholia
Mochizuki Y, Takenawa T.; ''Novel inositol polyphosphate 5-phosphatase localizes at membrane ruffles.''; PubMedEurope PMCScholia
Hidaka K, Caffrey JJ, Hua L, Zhang T, Falck JR, Nickel GC, Carrel L, Barnes LD, Shears SB.; ''An adjacent pair of human NUDT genes on chromosome X are preferentially expressed in testis and encode two new isoforms of diphosphoinositol polyphosphate phosphohydrolase.''; PubMedEurope PMCScholia
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Fridy PC, Otto JC, Dollins DE, York JD.; ''Cloning and characterization of two human VIP1-like inositol hexakisphosphate and diphosphoinositol pentakisphosphate kinases.''; PubMedEurope PMCScholia
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Yang X, Safrany ST, Shears SB.; ''Site-directed mutagenesis of diphosphoinositol polyphosphate phosphohydrolase, a dual specificity NUDT enzyme that attacks diadenosine polyphosphates and diphosphoinositol polyphosphates.''; PubMedEurope PMCScholia
Nogimori K, Hughes PJ, Glennon MC, Hodgson ME, Putney JW, Shears SB.; ''Purification of an inositol (1,3,4,5)-tetrakisphosphate 3-phosphatase activity from rat liver and the evaluation of its substrate specificity.''; PubMedEurope PMCScholia
Clarke LA.; ''The mucopolysaccharidoses: a success of molecular medicine.''; PubMedEurope PMCScholia
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Irvine RF, Schell MJ.; ''Back in the water: the return of the inositol phosphates.''; PubMedEurope PMCScholia
Harita Y, Kurihara H, Kosako H, Tezuka T, Sekine T, Igarashi T, Ohsawa I, Ohta S, Hattori S.; ''Phosphorylation of Nephrin Triggers Ca2+ Signaling by Recruitment and Activation of Phospholipase C-{gamma}1.''; PubMedEurope PMCScholia
Hwang JI, Oh YS, Shin KJ, Kim H, Ryu SH, Suh PG.; ''Molecular cloning and characterization of a novel phospholipase C, PLC-eta.''; PubMedEurope PMCScholia
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Saiardi A, Nagata E, Luo HR, Snowman AM, Snyder SH.; ''Identification and characterization of a novel inositol hexakisphosphate kinase.''; PubMedEurope PMCScholia
Leslie NR, McLennan AG, Safrany ST.; ''Cloning and characterisation of hAps1 and hAps2, human diadenosine polyphosphate-metabolising Nudix hydrolases.''; PubMedEurope PMCScholia
Patterson RL, van Rossum DB, Nikolaidis N, Gill DL, Snyder SH.; ''Phospholipase C-gamma: diverse roles in receptor-mediated calcium signaling.''; PubMedEurope PMCScholia
Mulugu S, Bai W, Fridy PC, Bastidas RJ, Otto JC, Dollins DE, Haystead TA, Ribeiro AA, York JD.; ''A conserved family of enzymes that phosphorylate inositol hexakisphosphate.''; PubMedEurope PMCScholia
Zhou Y, Wing MR, Sondek J, Harden TK.; ''Molecular cloning and characterization of PLC-eta2.''; PubMedEurope PMCScholia
Safrany ST, Caffrey JJ, Yang X, Bembenek ME, Moyer MB, Burkhart WA, Shears SB.; ''A novel context for the 'MutT' module, a guardian of cell integrity, in a diphosphoinositol polyphosphate phosphohydrolase.''; PubMedEurope PMCScholia
Han SY, Kato H, Kato S, Suzuki T, Shibata H, Ishii S, Shiiba K, Matsuno S, Kanamaru R, Ishioka C.; ''Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay.''; PubMedEurope PMCScholia
Drayer AL, Pesesse X, De Smedt F, Woscholski R, Parker P, Erneux C.; ''Cloning and expression of a human placenta inositol 1,3,4,5-tetrakisphosphate and phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase.''; PubMedEurope PMCScholia
Wang H, Falck JR, Hall TM, Shears SB.; ''Structural basis for an inositol pyrophosphate kinase surmounting phosphate crowding.''; PubMedEurope PMCScholia
Baldassare JJ, Henderson PA, Fisher GJ.; ''Isolation and characterization of one soluble and two membrane-associated forms of phosphoinositide-specific phospholipase C from human platelets.''; PubMedEurope PMCScholia
Yang X, Shears SB.; ''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.''; PubMedEurope PMCScholia
Carozzi AJ, Kriz RW, Webster C, Parker PJ.; ''Identification, purification and characterization of a novel phosphatidylinositol-specific phospholipase C, a third member of the beta subfamily.''; PubMedEurope PMCScholia
Jefferson AB, Majerus PW.; ''Properties of type II inositol polyphosphate 5-phosphatase.''; PubMedEurope PMCScholia
Leung DW, Tompkins C, Brewer J, Ball A, Coon M, Morris V, Waggoner D, Singer JW.; ''Phospholipase C delta-4 overexpression upregulates ErbB1/2 expression, Erk signaling pathway, and proliferation in MCF-7 cells.''; PubMedEurope PMCScholia
Chang SC, Miller AL, Feng Y, Wente SR, Majerus PW.; ''The human homolog of the rat inositol phosphate multikinase is an inositol 1,3,4,6-tetrakisphosphate 5-kinase.''; PubMedEurope PMCScholia
Jhon DY, Lee HH, Park D, Lee CW, Lee KH, Yoo OJ, Rhee SG.; ''Cloning, sequencing, purification, and Gq-dependent activation of phospholipase C-beta 3.''; PubMedEurope PMCScholia
Alcázar-Román AR, Wente SR.; ''Inositol polyphosphates: a new frontier for regulating gene expression.''; PubMedEurope PMCScholia
Pawełczyk T, Matecki A.; ''Expression, purification and kinetic properties of human recombinant phospholipase C delta 3.''; PubMedEurope PMCScholia
Lopez I, Mak EC, Ding J, Hamm HE, Lomasney JW.; ''A novel bifunctional phospholipase c that is regulated by Galpha 12 and stimulates the Ras/mitogen-activated protein kinase pathway.''; PubMedEurope PMCScholia
Deleu S, Choi K, Pesesse X, Cho J, Sulis ML, Parsons R, Shears SB.; ''Physiological levels of PTEN control the size of the cellular Ins(1,3,4,5,6)P(5) pool.''; PubMedEurope PMCScholia
Laxminarayan KM, Chan BK, Tetaz T, Bird PI, Mitchell CA.; ''Characterization of a cDNA encoding the 43-kDa membrane-associated inositol-polyphosphate 5-phosphatase.''; PubMedEurope PMCScholia
York JD, Veile RA, Donis-Keller H, Majerus PW.; ''Cloning, heterologous expression, and chromosomal localization of human inositol polyphosphate 1-phosphatase.''; PubMedEurope PMCScholia
Saiardi A, Caffrey JJ, Snyder SH, Shears SB.; ''The inositol hexakisphosphate kinase family. Catalytic flexibility and function in yeast vacuole biogenesis.''; PubMedEurope PMCScholia
Lee CW, Park DJ, Lee KH, Kim CG, Rhee SG.; ''Purification, molecular cloning, and sequencing of phospholipase C-beta 4.''; PubMedEurope PMCScholia
Norris FA, Atkins RC, Majerus PW.; ''The cDNA cloning and characterization of inositol polyphosphate 4-phosphatase type II. Evidence for conserved alternative splicing in the 4-phosphatase family.''; PubMedEurope PMCScholia
Bunney TD, Katan M.; ''Phosphoinositide signalling in cancer: beyond PI3K and PTEN.''; PubMedEurope PMCScholia
Banno Y, Yada Y, Nozawa Y.; ''Purification and characterization of membrane-bound phospholipase C specific for phosphoinositides from human platelets.''; PubMedEurope PMCScholia
Cheng HF, Jiang MJ, Chen CL, Liu SM, Wong LP, Lomasney JW, King K.; ''Cloning and identification of amino acid residues of human phospholipase C delta 1 essential for catalysis.''; PubMedEurope PMCScholia
Song C, Hu CD, Masago M, Kariyai K, Yamawaki-Kataoka Y, Shibatohge M, Wu D, Satoh T, Kataoka T.; ''Regulation of a novel human phospholipase C, PLCepsilon, through membrane targeting by Ras.''; PubMedEurope PMCScholia
Ho MW, Yang X, Carew MA, Zhang T, Hua L, Kwon YU, Chung SK, Adelt S, Vogel G, Riley AM, Potter BV, Shears SB.; ''Regulation of Ins(3,4,5,6)P(4) signaling by a reversible kinase/phosphatase.''; PubMedEurope PMCScholia
Caricasole A, Sala C, Roncarati R, Formenti E, Terstappen GC.; ''Cloning and characterization of the human phosphoinositide-specific phospholipase C-beta 1 (PLC beta 1).''; PubMedEurope PMCScholia
Chi Y, Zhou B, Wang WQ, Chung SK, Kwon YU, Ahn YH, Chang YT, Tsujishita Y, Hurley JH, Zhang ZY.; ''Comparative mechanistic and substrate specificity study of inositol polyphosphate 5-phosphatase Schizosaccharomyces pombe Synaptojanin and SHIP2.''; PubMedEurope PMCScholia
Thorsell AG, Persson C, Voevodskaya N, Busam RD, Hammarström M, Gräslund S, Gräslund A, Hallberg BM.; ''Structural and biophysical characterization of human myo-inositol oxygenase.''; PubMedEurope PMCScholia
Zhang X, Jefferson AB, Auethavekiat V, Majerus PW.; ''The protein deficient in Lowe syndrome is a phosphatidylinositol-4,5-bisphosphate 5-phosphatase.''; PubMedEurope PMCScholia
Lin H, Fridy PC, Ribeiro AA, Choi JH, Barma DK, Vogel G, Falck JR, Shears SB, York JD, Mayr GW.; ''Structural analysis and detection of biological inositol pyrophosphates reveal that the family of VIP/diphosphoinositol pentakisphosphate kinases are 1/3-kinases.''; PubMedEurope PMCScholia
Arner RJ, Prabhu KS, Reddy CC.; ''Molecular cloning, expression, and characterization of myo-inositol oxygenase from mouse, rat, and human kidney.''; PubMedEurope PMCScholia
Norris FA, Auethavekiat V, Majerus PW.; ''The isolation and characterization of cDNA encoding human and rat brain inositol polyphosphate 4-phosphatase.''; PubMedEurope PMCScholia
Draskovic P, Saiardi A, Bhandari R, Burton A, Ilc G, Kovacevic M, Snyder SH, Podobnik M.; ''Inositol hexakisphosphate kinase products contain diphosphate and triphosphate groups.''; PubMedEurope PMCScholia
Park D, Jhon DY, Kriz R, Knopf J, Rhee SG.; ''Cloning, sequencing, expression, and Gq-independent activation of phospholipase C-beta 2.''; PubMedEurope PMCScholia
Monserrate JP, York JD.; ''Inositol phosphate synthesis and the nuclear processes they affect.''; PubMedEurope PMCScholia
Chi H, Tiller GE, Dasouki MJ, Romano PR, Wang J, O'keefe RJ, Puzas JE, Rosier RN, Reynolds PR.; ''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.''; PubMedEurope PMCScholia
McAllister G, Whiting P, Hammond EA, Knowles MR, Atack JR, Bailey FJ, Maigetter R, Ragan CI.; ''cDNA cloning of human and rat brain myo-inositol monophosphatase. Expression and characterization of the human recombinant enzyme.''; PubMedEurope PMCScholia
Zhang X, Hartz PA, Philip E, Racusen LC, Majerus PW.; ''Cell lines from kidney proximal tubules of a patient with Lowe syndrome lack OCRL inositol polyphosphate 5-phosphatase and accumulate phosphatidylinositol 4,5-bisphosphate.''; PubMedEurope PMCScholia
Schmid AC, Wise HM, Mitchell CA, Nussbaum R, Woscholski R.; ''Type II phosphoinositide 5-phosphatases have unique sensitivities towards fatty acid composition and head group phosphorylation.''; PubMedEurope PMCScholia
Wilson MP, Majerus PW.; ''Isolation of inositol 1,3,4-trisphosphate 5/6-kinase, cDNA cloning and expression of the recombinant enzyme.''; PubMedEurope PMCScholia
York JD.; ''Regulation of nuclear processes by inositol polyphosphates.''; PubMedEurope PMCScholia
Nalaskowski MM, Deschermeier C, Fanick W, Mayr GW.; ''The human homologue of yeast ArgRIII protein is an inositol phosphate multikinase with predominantly nuclear localization.''; PubMedEurope PMCScholia
Choi JH, Williams J, Cho J, Falck JR, Shears SB.; ''Purification, sequencing, and molecular identification of a mammalian PP-InsP5 kinase that is activated when cells are exposed to hyperosmotic stress.''; PubMedEurope PMCScholia
Kouchi Z, Shikano T, Nakamura Y, Shirakawa H, Fukami K, Miyazaki S.; ''The role of EF-hand domains and C2 domain in regulation of enzymatic activity of phospholipase Czeta.''; PubMedEurope PMCScholia
Rogers NT, Hobson E, Pickering S, Lai FA, Braude P, Swann K.; ''Phospholipase Czeta causes Ca2+ oscillations and parthenogenetic activation of human oocytes.''; PubMedEurope PMCScholia
Kavanaugh WM, Pot DA, Chin SM, Deuter-Reinhard M, Jefferson AB, Norris FA, Masiarz FR, Cousens LS, Majerus PW, Williams LT.; ''Multiple forms of an inositol polyphosphate 5-phosphatase form signaling complexes with Shc and Grb2.''; PubMedEurope PMCScholia
Ohnishi T, Ohba H, Seo KC, Im J, Sato Y, Iwayama Y, Furuichi T, Chung SK, Yoshikawa T.; ''Spatial expression patterns and biochemical properties distinguish a second myo-inositol monophosphatase IMPA2 from IMPA1.''; PubMedEurope PMCScholia
Cantz M, Gehler J.; ''The mucopolysaccharidoses: inborn errors of glycosaminoglycan catabolism.''; PubMedEurope PMCScholia
Caffrey JJ, Safrany ST, Yang X, Shears SB.; ''Discovery of molecular and catalytic diversity among human diphosphoinositol-polyphosphate phosphohydrolases. An expanding Nudt family.''; PubMedEurope PMCScholia
Brehm MA, Schenk TM, Zhou X, Fanick W, Lin H, Windhorst S, Nalaskowski MM, Kobras M, Shears SB, Mayr GW.; ''Intracellular localization of human Ins(1,3,4,5,6)P5 2-kinase.''; PubMedEurope PMCScholia
Glycosaminoglycans (GAGs) are long, unbranched polysaccharides containing a repeating disaccharide unit composed of a hexosamine (either N-acetylgalactosamine (GalNAc) or N-acetylglucosamine (GlcNAc)) and a uronic acid (glucuronate or iduronate). They can be heavily sulfated. GAGs are located primarily in the extracellular matrix (ECM) and on cell membranes, acting as a lubricating fluid for joints and as part of signalling processes. They have structural roles in connective tissue, cartilage, bone and blood vessels (Esko et al. 2009). GAGs are degraded in the lysosome as part of their natural turnover. Defects in the lysosomal enzymes responsible for the metabolism of membrane-associated GAGs lead to lysosomal storage diseases called mucopolysaccharidoses (MPS). MPSs are characterised by the accumulation of GAGs in lysosomes resulting in chronic, progressively debilitating disorders that in many instances lead to severe psychomotor retardation and premature death (Cantz & Gehler 1976, Clarke 2008). The biosynthesis and breakdown of the main GAGs (hyaluronate, keratan sulfate, chondroitin sulfate, dermatan sulfate and heparan sulfate) is described here.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
Inositol-trisphosphate 3-kinase A (ITPKA), B (ITPKB), and C (ITPKC) phosphorylate inositol 1,4,5-trisphosphate (I(1,4,5)P3) to inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) (Dewaste et al. 2003).
Inositol monophosphatase 1 (IMPA1) and 2 (IMPA2) homodimers dephosphorylate inositol 1-phosphate (I1P) to inositol (Ins). In vitro, IMPA1 and 2 differ in their pH optima and IMPA1 has a significantly greater activity on IP4 than does IMPA2 (McAllister et al. 1992, Ohnishi et al. 2007).
Inositol 1,3,4,5,6-pentakisphosphate I(1,3,4,5,6)P5 translocates from the endoplasmic reticulum (ER) lumen to the cytosol (Nalaskowski et al. 2002, Ho et al. 2002, Brehm et al. 2007).
In the nucleus, inositol hexakisphosphate kinase 1 (IP6K1) and 2 (IP6K2) phosphorylate 1-diphospho-2,3,4,5,6-pentakisphosphate (1-PP-IP5) to make inositol 1,5-bisdiphospho-2,3,4,6-tetrakisphosphate (1,5-(PP)2-IP4) (Saiardi et al. 2001, Mulugu et al. 2007).
Inositol hexakisphosphate kinase 1 (IP6K1) and 3 (IP6K3) phosphorylate inositol 5-diphospho-1,2,3,4,6-pentakisphosphate (5-PP-IP5) to inositol 5-triphospho- 1,2,3,4,6-pentakisphosphate (5-PPP-IP5).
The following lists the above proteins with their corresponding literature references: IP6K1 (Saiardi et al. 2001, Draskovic et al. 2008) and IP6K3 (Saiardi et al. 2001, Draskovic et al. 2008).
Inositol 1,3,4,5,6-pentakisphosphate (I(1,3,4,5,6)P5) translocates from the endoplasmic reticulum (ER) lumen to the nucleus (Verbsky et al. 2002, Brehm et al. 2007, Choi et al. 2007).
Inositol 1,3,4,5,6-pentakisphosphate I(1,3,4,5,6)P5 translocates from the nucleus to the cytosol (Nalaskowski et al. 2002; Ho et al. 2002, Brehm et al. 2007).
In the endoplasmic reticulum (ER) lumen, multiple inositol polyphosphate phosphatase 1 (MINPP1) dephosphorylates inositol 1,3,4,5,6-pentakisphosphate (I(1,3,4,5,6)P5) to inositol 1,4,5,6-tetrakisphosphate (I(1,4,5,6)P4) (Caffrey et al. 1999, Chi et al. 1999).
Diphosphoinositol polyphosphate phosphohydrolases (DIPP), also known as nucleoside diphosphate-linked moiety X motif (NUDT) proteins, dephosphorylate inositol bisdiphospho-tetrakisphosphate ((PP)2-IP4) to inositol 5-diphospho-1,2,3,4,6-pentakisphosphate (5-PP-IP5). The NUDT proteins involved are: nucleoside diphosphate-linked moiety X motif 3 (NUDT3), 4 (NUDT4), 10 (NUDT10), and 11 (NUDT11). The reactants consumed are: inositol 1,5-bisdiphospho-2,3,4,6-tetrakisphosphate (1,5-(PP)2-IP4) and inositol 3,5-bisdiphospho-1,2,4,6-tetrakisphosphate (3,5-(PP)2-IP4).
The following lists the above proteins with their corresponding literature references: NUDT3 (Safrany et al. 1999, Safrany et al. 1998, Yang et al. 1999, Caffrey et al. 2000), NUDT4 (Caffrey et al. 2000), NUDT10 (Leslie et al. 2002, Hidaka et al. 2002) and NUDT11 (Leslie et al. 2002, Hidaka et al. 2002).
Diphosphoinositol polyphosphate phosphohydrolase 2, also known as nucleoside diphosphate-linked moiety X motif 4 (NUDT4), dephosphorylates diphospho- tetrakisphosphate (PP-IP4) to inositol 1,3,4,5,6-pentakisphosphate (I(1,3,4,5,6)P5). The products made are: inositol 5-diphospho-1,3,4,6-tetrakisphosphate (5-PP-IP4); inositol 1-diphospho-3,4,5,6-tetrakisphosphate (1-PP-IP4); and inositol 3-diphospho-1,4,5,6-tetrakisphosphate (3-PP-IP4).
The following lists the above protein with its corresponding literature references: NUDT4 (Saiardi et al. 2001, Saiardi et al. 2000).
A group of inositol phosphatases dephosphorylate inositol 1,4,5-trisphosphate (I(1,4,5)P3) to inositol 1,4-bisphosphate (I(1,4)P2). The group of inositol phosphatases involved are: inositol polyphosphate 5-phosphatase OCRL-1 (OCRL), phosphatidylinositol 4,5-bisphosphate 5-phosphatase A (INPP5J), and synaptic inositol-1,4,5-trisphosphate 5-phosphatase 1 (SYNJ1).
The following lists the above proteins with their corresponding literature references: OCRL (Zhang et al. 1995, Zhang et al. 1998, Schmid et al. 2004); INPP5J (Mochizuki & Thompson 1999); SYNJ1 (Schmid et al. 2004).
In the nucleus, inositol-pentakisphosphate 2-kinase (IPPK - also known as IP5-2K) phosphorylates inositol 1,3,4,5,6-pentakisphosphate (I(1,3,4,5,6)P5) to inositol 1,2,3,4,5,6-hexakisphosphate (IP6) (Verbsky et al. 2002, Brehm et al. 2007, Choi et al. 2007).
At the plasma membrane, a group of phospholipase C (“PLC(bz))� proteins hydrolyse phosphatidylinositol 4,5 bisphosphate (PI(4,5)P2) to inositol 1,4,5 trisphosphate (I(1,4,5)P3) and diacylglycerol (DAG). This group of phospholipase C proteins lack a PH domain and so are is cytosolic. Their C2 domains bind to PI(4,5)P2 at the membrane. The PLC-beta proteins are thought to be responsible for the majority of PI(4,5)P2 hydrolysis.
The phospholipase C isoforms involved and their corresponding literature references are: phosphoinositide phospholipase C beta-1 (PLCB1) (Caricasole et al. 2000, Jhon et al. 1993, Park et al. 1992); beta-2 (PLCB2) (Jhon et al. 1993, Park et al. 1992); beta-3 (PLCB3) (Carozzi et al. 1992, Jhon et al. 1993); beta-4 (PLCB4) (Alvarez et al. 1995, Lee et al. 1993); and zeta-1 (PLCZ1) (Kouchi et al. 2005, Rogers et al. 2004).
Inositolpentakisphosphate 2-kinase (IPPK), also known as IP52K, phosphorylates inositol 1,3,4,5,6-pentakisphosphate (I(1,3,4,5,6)P5) to inositol 1,2,3,4,5,6-hexakisphosphate (IP6) (Verbski et al. 2002, Brehm et al. 2007, Choi et al. 2007).
Type I (INPP4A) and type II inositol-3,4-bisphosphate 4-phosphatase (INPP4B) dephosphorylate inositol 1,3,4-trisphosphate (I(1,3,4)P3) to inositol 1,3-bisphosphate (I(1,3)P2) (Norris et al. 1995, Norris et al. 1997).
In the nucleus, inositol hexakisphosphate kinase 1 (IP6K1) and 2 (IP6K2) phosphorylate inositol 1,3,4,5,6-pentakisphosphate (I(1,3,4,5,6)P5) to inositol 5-diphospho-(1,3,4,6)-tetrakisphosphate (5-PP-IP4) (Saiardi et al. 2001, Saiardi et al. 2000, Draskovic et al. 2008).
Inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinase 1/2 (PPIP5K1) and 2 (PPIP5K2) phosphorylate inositol 5-diphospho-1,2,3,4,6-pentakisphosphate (5-PP-IP5) to inositol 1,5-bisdiphospho-2,3,4,6-tetrakisphosphate (1,5-(PP)2-IP4) (Fridy et al. 2007, Mulugu et al. 2007, Choi et al. 2007, Lin et al. 2009).
Inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) translocates from the cytosol to the endoplasmic reticulum (ER) lumen (Caffrey et al. 1999, Chi et al. 1999).
Inositol 1,4,5,6-tetrakisphosphate (I(1,4,5,6)P4) translocates from the endoplasmic reticulum (ER) lumen to the nucleus (Caffrey et al. 1999, Chi et al. 1999, Nalaskowski et al. 2002).
Inositol hexakisphosphate kinase 1 (IP6K1) and 3 (IP6K3) phosphorylate inositol 1-diphospho-3,4,5,6-tetrakisphosphate (1-PP-IP4) to form inositol 1,5-bisdiphospho-3,4,6-trisphosphate (1,5-(PP)2-IP3) (Saiardi et al. 2001, Saiardi et al. 2000, Draskovic et al. 2008).
Inositol hexakisphosphate kinase 1 (IP6K1) and 3 (IP6K3) phosphorylate 1-diphospho-2,3,4,5,6-pentakisphosphate (1-PP-IP5) to form inositol 1,5-bisdiphospho-2,3,4,6-tetrakisphosphate (1,5-(PP)2-IP4) (Saiardi et al. 2001, Mulugu et al. 2007).
Inositol 1,3,4,5,6-pentakisphosphate I(1,3,4,5,6)P5 translocates from the cytosol to the endoplasmic reticulum (ER) lumen (Caffrey et al. 1999, Chi et al. 1999).
Diphosphoinositol polyphosphate phosphohydrolases (DIPP), also known as nucleoside diphosphate-linked moiety X motif (NUDT) proteins, dephosphorylate inositol 5-diphospho-1,2,3,4,6-pentakisphosphate (5-PP-IP5) to inositol 1,2,3,4,5,6-hexakisphosphate (IP6). The NUDT proteins involved are: nucleoside diphosphate-linked moiety X motif 3 (NUDT3), 4 (NUDT4), 10 (NUDT10), and 11 (NUDT11).
The following lists the above proteins with their corresponding literature references: NUDT3 (Safrany et al. 1999, Safrany et al. 1998, Yang et al. 1999, Caffrey et al. 2000), NUDT4 (Caffrey et al. 2000), NUDT10 (Leslie et al. 2002, Hidaka et al. 2002) and NUDT11 (Leslie et al. 2002, Hidaka et al. 2002).
In the endoplasmic reticulum (ER) lumen, multiple inositol polyphosphate phosphatase 1 (MINPP1) dephosphorylates inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) to inositol 1,4,5-trisphosphate (I(1,4,5)P3) (Caffrey et al. 1999, Chi et al. 1999).
Type I (INPP4A) and type II inositol-3,4-bisphosphate 4-phosphatase (INPP4B) dephosphorylate inositol 3,4-bisphosphate (I(3,4)P2) to inositol 3-phosphate (I3P) (Norris et al. 1995, Norris et al. 1997).
Phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase aka phosphatase and tensin homolog (PTEN) dephosphorylates inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) to inositol 1,4,5-trisphosphate (I(1,4,5)P3) (Maehama & Dixon 1998, Han et al. 2000).
In the nucleus, inositol hexakisphosphate kinase 1 (IP6K1) and 2 (IP6K2) phosphorylate inositol 1,2,3,4,5,6-hexakisphosphate (IP6) to inositol 5-diphospho-1,2,3,4,6-pentakisphosphate (5-PP-IP5).
The following lists the above proteins with their corresponding literature references: IP6K1 (Saiardi et al. 2001, Mulugu et al. 2007, Draskovic et al. 2008) and IP6K2 (Saiardi et al. 2001, Mulugu et al. 2007, Draskovic et al. 2008).
Inositol monophosphatase 1 (IMPA1) and 2 (IMPA2) homodimers dephosphorylate inositol 3-phosphate (I3P) to inositol (Ins). In vitro, IMPA1 and 2 differ in their pH optima and IMPA1 has a significantly greater activity on IP4 than does IMPA2 (Ohnishi et al. 2007).
Inositol monophosphatase 1 (IMPA1) and 2 (IMPA2) homodimers dephosphorylate inositol 4-phosphate (I4P) to inositol (Ins). In vitro, IMPA1 and 2 differ in their pH optima and IMPA1 has a significantly greater activity on IP4 than does IMPA2 (Ohnishi et al. 2007).
1-diphospho-2,3,4,5,6-pentakisphosphate (1-PP-IP5) and 3-diphospho-1,2,4,5,6-pentakisphosphate (3-PP-IP5) translocate from the cytosol to the nucleus (Saiardi et al. 2001, Mulugu et al. 2007).
Type II inositol-1,4,5-trisphosphate 5-phosphatase (INPP5B) is attached to the plasma membrane where it dephosphorylates inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) to inositol 1,3,4-trisphosphate (I(1,3,4)P3 (Jefferson & Majerus 1995, Ross et al. 1991, Schmid et al. 2004). INPP5B is isoprenylated at its C-terminus for membrane attachment.
At the endoplasmic reticulum (ER) membrane, 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-4 (PLCD4) and phospholipase D4 (PLD4) hydrolyse phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) to inositol 1,4,5-trisphosphate (I(1,4,5)P3) and diacylglycerol (DAG). Both lipases are thought to require three Ca2+ ions per subunit for activity. PLD4 is attached to the ER membrane via its PH domain while its C2 domain binds to the PI(4,5)P2 in the membrane (Lee et al. 2004). Overexpression or dysregulated expression of PLCD4 may initiate oncogenesis in certain tissues through upregulation of ErbB expression and activation of ERK pathway. PLCD4 can therefore be a useful tumor marker for breast or testicular cancer tissues (Leung et al. 2004).
Inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinase 1/2 (PPIP5K1) and 2 (PPIP5K2) phosphorylate inositol 1,2,3,4,5,6-hexakisphosphate (IP6) to inositol 1-diphospho-2,3,4,5,6-pentakisphosphate (1-PP-IP5)) (Fridy et al. 2007, Mulugu et al. 2007, Choi et al. 2007, Lin et al. 2009; Wang et al. 2011).
Inositol 1,4,5-trisphosphate (I(1,4,5)P3) translocates from the endoplasmic reticulum (ER) lumen to the cytosol (Caffrey et al. 1999, Chi et al. 1999).
A group of inositol phosphatases and the broad specificity enzyme inositol-tetrakisphosphate 1-kinase (ITPK1) dephosphorylate inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) to inositol 1,3,4-trisphosphate (I(1,3,4)P3). The group of inositol phosphatases involved are: inositol polyphosphate 5-phosphatase OCRL-1 (OCRL), phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1 (INPP5D) aka SHIP1, phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 2 (INPPL1) aka SHIP2, phosphatidylinositol 4,5-bisphosphate 5-phosphatase A (INPP5J) aka PIPP, and synaptic inositol-1,4,5-trisphosphate 5-phosphatase 1 (SYNJ1).
The following lists the above proteins with their corresponding literature references: OCRL (Chang et al. 2002, Zhang et al. 1995, Zhang et al. 1998, Schmid et al. 2004); INPP5D (Drayer et al. 1996, Kavanaugh et al. 1996); INPPL1 (Chi et al. 2004); INPP5J (Mochizuki & Thompson 1999); SYNJ1 (Schmid et al. 2004); ITPK1 (Ho et al. 2002).
Inositol 1,5-bisdiphospho-2,3,4,6-tetrakisphosphate (1,5-(PP)2-IP4) and inositol 3,5-bisdiphospho-1,2,4,6-tetrakisphosphate (3,5-(PP)2-IP4) translocate from the nucleus to the cytosol (Leslie et al. 2002).
A group of phospholipase C proteins (“PLC(degh)�) bind to the plasma membrane via their PH domains. These phospholipases hydrolyse phosphatidylinositol 4,5 bisphosphate (PI(4,5)P2) to inositol 1,4,5 trisphosphate (I(1,4,5)P3) and diacylglycerol (DAG). The C2 domains of the enzymes bind to PI(4,5)P2 at the membrane.
The phospholipase C isoforms involved and their corresponding literature references are: phosphoinositide phospholipase C delta-1(PLCD1) (Cheng et al. 1995); epsilon-1 (PLCE1) (Song et al. 2001, Lopez et al. 2001); delta-3 (PLCD3) (Pawelczyk & Matecki 1997); gamma-1 (PLCG1) (Harita et al. 2009, Baldassare et al. 1989); gamma-2 (PLCG2) (Banno et al. 1988); eta-1 (PLCH1) (Hwang et al. 2005); and eta-2 (PLCH2) (Zhou et al 2005).
Type I inositol-1,4,5-trisphosphate 5-phosphatase (INPP5A) and the Type II phosphatase (INPP5B) are isoprenylated to the plasma membrane and act as a lipid anchor. Here they dephosphorylate inositol 1,4,5-trisphosphate (I(1,4,5)P3) to inositol 1,4-bisphosphate I(1,4)P2. ).
The following lists the above proteins with their corresponding literature references: INPP5A (Laxminarayan et al. 1994); INPP5B (Jefferson & Majerus 1995, Ross et al. 1991, Schmid et al. 2004).
In the nucleus, inositol hexakisphosphate kinase 1 (IP6K1) and 2 (IP6K2) phosphorylate inositol 5-diphospho-1,2,3,4,6-pentakisphosphate (5-PP-IP5) to inositol 5-triphospho- 1,2,3,4,6-pentakisphosphate (5-PPP-IP5) (Saiardi et al. 2001, Draskovic et al. 2008) and IP6K2 (Saiardi et al. 2001, Draskovic et al. 2008). While this reaction has been demonstrated to occur in vitro, the extent to which it occurs in vivo is less clear.
In the endoplasmic reticulum (ER) lumen, multiple inositol polyphosphate phosphatase 1 (MINPP1) dephosphorylates 1,2,3,4,5,6-hexakisphosphate (IP6) to inositol 1,2,4,5,6-pentakisphosphate (I(1,2,4,5,6)P5) (Caffrey et al. 1999, Chi et al. 1999, Deleu et al. 2006, Nogimori et al. 1991).
Inositol hexakisphosphate kinase 1 (IP6K1) and 3 (IP6K3) phosphorylate inositol 1,2,3,4,5,6-hexakisphosphate (IP6) to inositol 5-diphospho-1,2,3,4,6-pentakisphosphate (5-PP-IP5).
The following lists the above proteins with their corresponding literature references: IP6K1 (Saiardi et al. 2001, Mulugu et al. 2007, Draskovic et al. 2008; Lin et al. 2009) and IP6K3 (Saiardi et al. 2001, Draskovic et al. 2008).
In the nucleus, inositol hexakisphosphate kinase 1 (IP6K1) and 2 (IP6K2) phosphorylate5-diphospho-1,3,4,6-tetrakisphosphate (5-PP-IP4) to inositol 1,5-bisdiphospho-3,4,6-trisphosphate (1,5-(PP)2-IP3) (Saiardi et al. 2001, Saiardi et al. 2000, Draskovic et al. 2008).
Diphosphoinositol polyphosphate phosphohydrolases, also known as nucleoside diphosphate-linked moiety X motif (NUDT) proteins, dephosphorylate inositol diphospho-pentakisphosphate (PP-IP5) to inositol 1,2,3,4,5,6-hexakisphosphate (IP6). The NUDT proteins involved are: nucleoside diphosphate-linked moiety X motif 3 (NUDT3), 4 (NUDT4), 10 (NUDT10), and 11 (NUDT11). The reactants consumed are: inositol 1-diphospho-2,3,4,5,6-pentakisphosphate (1-PP-IP5) and 3-diphospho-1,2,4,5,6-pentakisphosphate (3-PP-IP5).
The following lists the above proteins with their corresponding literature references: NUDT3 (Safrany et al. 1999, Safrany et al. 1998, Yang et al. 1999, Caffrey et al. 2000), NUDT4 (Caffrey et al. 2000), NUDT10 (Leslie et al. 2002, Hidaka et al. 2002) and NUDT11 (Leslie et al. 2002, Hidaka et al. 2002).
Diphosphoinositol polyphosphate phosphohydrolases (DIPP), also known as nucleoside diphosphate-linked moiety X motif (NUDT) proteins, dephosphorylate inositol bisdiphospho-tetrakisphosphate ((PP)2-IP4) to inositol diphospho-pentakisphosphate (PP-IP5). The NUDT proteins involved are: nucleoside diphosphate-linked moiety X motif 3 (NUDT3), 4 (NUDT4), 10 (NUDT10), and 11 (NUDT11). The reactants consumed are: inositol 1,5-bisdiphospho-2,3,4,6-tetrakisphosphate (1,5-(PP)2-IP4) and inositol 3,5-bisdiphospho-1,2,4,6-tetrakisphosphate (3,5-(PP)2-IP4). The products made are: inositol 1-diphospho-2,3,4,5,6-pentakisphosphate (1-PP-IP5) and 3-diphospho-1,2,4,5,6-pentakisphosphate (3-PP-IP5).
The following lists the above proteins with their corresponding literature references: NUDT3 (Safrany et al. 1999, Safrany et al. 1998, Yang et al. 1999, Caffrey et al. 2000), NUDT4 (Caffrey et al. 2000), NUDT10 (Leslie et al. 2002, Hidaka et al. 2002) and NUDT11 (Leslie et al. 2002, Hidaka et al. 2002).
Inositol oxidase (MIOX) catalyses the oxidation of inositol (Ins) to glucuronic acid (GlcA). MIOX binds two Fe2+ ions as cofactor (Arner et al. 2004, Thorsell et al. 2008).
MTMR7 binds to MTMR9, an enzymatically inactive myotubularin family member, which results in increased enzymatic activity of MTMR7. Almost all MTMR7 in the cell is present in the complex with MTMR9 (Mochizuki and Majerus 2003).
Formation of a complex with MTMR9 results in 2- to 5-fold increase in MTMR7 inositol-1,3-bisphosphate 3-phosphatase catalytic activity (Mochizuki and Majerus 2003).
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polyphosphate
5-phosphataseAnnotated Interactions
polyphosphate
5-phosphataseThe following lists the above proteins with their corresponding literature references: IP6K1 (Saiardi et al. 2001, Draskovic et al. 2008) and IP6K3 (Saiardi et al. 2001, Draskovic et al. 2008).
The following lists the above proteins with their corresponding literature references: NUDT3 (Safrany et al. 1999, Safrany et al. 1998, Yang et al. 1999, Caffrey et al. 2000), NUDT4 (Caffrey et al. 2000), NUDT10 (Leslie et al. 2002, Hidaka et al. 2002) and NUDT11 (Leslie et al. 2002, Hidaka et al. 2002).
The following lists the above protein with its corresponding literature references: NUDT4 (Saiardi et al. 2001, Saiardi et al. 2000).
The following lists the above proteins with their corresponding literature references: OCRL (Zhang et al. 1995, Zhang et al. 1998, Schmid et al. 2004); INPP5J (Mochizuki & Thompson 1999); SYNJ1 (Schmid et al. 2004).
The phospholipase C isoforms involved and their corresponding literature references are: phosphoinositide phospholipase C beta-1 (PLCB1) (Caricasole et al. 2000, Jhon et al. 1993, Park et al. 1992); beta-2 (PLCB2) (Jhon et al. 1993, Park et al. 1992); beta-3 (PLCB3) (Carozzi et al. 1992, Jhon et al. 1993); beta-4 (PLCB4) (Alvarez et al. 1995, Lee et al. 1993); and zeta-1 (PLCZ1) (Kouchi et al. 2005, Rogers et al. 2004).
The following lists the above proteins with their corresponding literature references: NUDT3 (Safrany et al. 1999, Safrany et al. 1998, Yang et al. 1999, Caffrey et al. 2000), NUDT4 (Caffrey et al. 2000), NUDT10 (Leslie et al. 2002, Hidaka et al. 2002) and NUDT11 (Leslie et al. 2002, Hidaka et al. 2002).
The following lists the above proteins with their corresponding literature references: IP6K1 (Saiardi et al. 2001, Mulugu et al. 2007, Draskovic et al. 2008) and IP6K2 (Saiardi et al. 2001, Mulugu et al. 2007, Draskovic et al. 2008).
The following lists the above proteins with their corresponding literature references: OCRL (Chang et al. 2002, Zhang et al. 1995, Zhang et al. 1998, Schmid et al. 2004); INPP5D (Drayer et al. 1996, Kavanaugh et al. 1996); INPPL1 (Chi et al. 2004); INPP5J (Mochizuki & Thompson 1999); SYNJ1 (Schmid et al. 2004); ITPK1 (Ho et al. 2002).
The phospholipase C isoforms involved and their corresponding literature references are: phosphoinositide phospholipase C delta-1(PLCD1) (Cheng et al. 1995); epsilon-1 (PLCE1) (Song et al. 2001, Lopez et al. 2001); delta-3 (PLCD3) (Pawelczyk & Matecki 1997); gamma-1 (PLCG1) (Harita et al. 2009, Baldassare et al. 1989); gamma-2 (PLCG2) (Banno et al. 1988); eta-1 (PLCH1) (Hwang et al. 2005); and eta-2 (PLCH2) (Zhou et al 2005).
The following lists the above proteins with their corresponding literature references: INPP5A (Laxminarayan et al. 1994); INPP5B (Jefferson & Majerus 1995, Ross et al. 1991, Schmid et al. 2004).
The following lists the above proteins with their corresponding literature references: IP6K1 (Saiardi et al. 2001, Mulugu et al. 2007, Draskovic et al. 2008; Lin et al. 2009) and IP6K3 (Saiardi et al. 2001, Draskovic et al. 2008).
The following lists the above proteins with their corresponding literature references: NUDT3 (Safrany et al. 1999, Safrany et al. 1998, Yang et al. 1999, Caffrey et al. 2000), NUDT4 (Caffrey et al. 2000), NUDT10 (Leslie et al. 2002, Hidaka et al. 2002) and NUDT11 (Leslie et al. 2002, Hidaka et al. 2002).
The following lists the above proteins with their corresponding literature references: NUDT3 (Safrany et al. 1999, Safrany et al. 1998, Yang et al. 1999, Caffrey et al. 2000), NUDT4 (Caffrey et al. 2000), NUDT10 (Leslie et al. 2002, Hidaka et al. 2002) and NUDT11 (Leslie et al. 2002, Hidaka et al. 2002).