Phosphoinositides metabolism (Homo sapiens)

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1766DAGBeta isotypes:Oculocerebrorenal syndrome of LowePI-3 kinase IIIMTMRsPtdIns(5)PMTM1PI-3 kinase IPIP-5 kinase alphaOCRLPLCB24-phosphatasePhosphateH2OPLCH1ATPDAGPIK3CGSHIP (1)PLCG1PI3K-C2αPTENPIKfyvePIP4P1PtdIns(4,5)P2PTENSACM1LPLCB1PIP-4 kinaseMTMR1P1P54P475P1P55PIP-5 kinase gammaPIP4K2APIP4K2CPIP4K2BDAGPtdIns(3,5)P2P5P1P3DAGPtdInsP1DAGPtdIns(3)PP1P3DAGPtdIns(3,4)P2P3P4P1DAGPtdIns(4)PP1P4DAGPtdIns(3,4,5)P3P3P1P4P5DAGIns(1,4,5)P3P5P1P4PIP4P2PIP-5 kinase betaPIK3CBPIK3CAPIK3CDPhospholipase CPLCB3PLCB4Gamma isotypes:PLCG2Epsilon isotype:PLCE1Delta isotypes:PLCD1PLCD3PLCD4Eta isotypes:Zeta isotype:PLCH2PLCZ1PIK3CGPI-3 kinase IPIK3CBPIK3CAPIK3CDPIP-5 kinase alphaPIP-5 kinase gammaPIP-5 kinase beta4-phosphatasePIP4P1PIP4P2PIP-4 kinasePIP4K2APIP4K2CPIP4K2BMTMR10MTMR11MTMR12MTMR2MTMR3MTMR4MTMR6MTMR7MTMR8MTMR9SBF2SBF1PIK3CGPI-3 kinase IPIK3CBPIK3CAPIK3CDPI-3 kinase IIPI3K-C2βPI3K-C2γPIK3C3PIK3R42ADPH+MTM1myotubular myopathy9Charcot-Marie-Tooth type 4B syndrome8Francois-Neetens fleck corneal dystrophy10


Description

Phosphatidylinositols are a family of lipids under the phosphatidylglyceride class. This pathway specifies several metabolic conversions between PIP, PIP2, PIP3 and other metabolites. Phosphorylation sites on the individual metabolites are drawn as states, with the location added as a number. The main interactions within this pathway are based on Figure 1 of Rusten et al, annotated with biochemical interaction database Rhea, and diseases (depicted in pink) with corresponding OMIM-identifiers.. Dashed lines depict proposed interactions which have not been characterised (yet)

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Ontology Terms

 

Bibliography

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  1. Rusten TE, Stenmark H; ''Analyzing phosphoinositides and their interacting proteins.''; Nat Methods, 2006 PubMed Europe PMC Scholia
  2. Backer JM; ''The regulation and function of Class III PI3Ks:novel roles for Vps34.''; Biochem J, 2008 PubMed Europe PMC Scholia
  3. Poli A, Zaurito AE, Abdul-Hamid S, Fiume R, Faenza I, Divecha N; ''Phosphatidylinositol 5 Phosphate (PI5P): From Behind the Scenes to the Front (Nuclear) Stage.''; Int J Mol Sci, 2019 PubMed Europe PMC Scholia
  4. Rohrschneider LR, Fuller JF, Wolf I, Liu Y, Lucas DM; ''Structure, function, and biology of SHIP proteins.''; Genes Dev, 2000 PubMed Europe PMC Scholia
  5. Ungewickell A, Hugge C, Kisseleva M, Chang SC, Zou J, Feng Y, Galyov EE, Wilson M, Majerus PW; ''''; , PubMed Europe PMC Scholia
  6. Rameh LE, Tolias KF, Duckworth BC, Cantley LC; ''A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate.''; Nature, 1997 PubMed Europe PMC Scholia
  7. Malek M, Kielkowska A, Chessa T, Anderson KE, Barneda D, Pir P, Nakanishi H, Eguchi S, Koizumi A, Sasaki J, Juvin V, Kiselev VY, Niewczas I, Gray A, Valayer A, Spensberger D, Imbert M, Felisbino S, Habuchi T, Beinke S, Cosulich S, Le Novère N, Sasaki T, Clark J, Hawkins PT, Stephens LR; ''PTEN Regulates PI(3,4)P2Signaling Downstream of Class I PI3K.''; Mol Cell, 2017 PubMed Europe PMC Scholia
  8. Bolino A, Muglia M, Conforti FL, LeGuern E, Salih MA, Georgiou DM, Christodoulou K, Hausmanowa-Petrusewicz I, Mandich P, Schenone A, Gambardella A, Bono F, Quattrone A, Devoto M, Monaco AP; ''Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2.''; Nat Genet, 2000 PubMed Europe PMC Scholia
  9. Laporte J, Hu LJ, Kretz C, Mandel JL, Kioschis P, Coy JF, Klauck SM, Poustka A, Dahl N; ''A gene mutated in X-linked myotubular myopathy definesa new putative tyrosine phosphatase family conserved in yeast.''; Nat Genet, 1996 PubMed Europe PMC Scholia
  10. Li S, Tiab L, Jiao X, Munier FL, Zografos L, Frueh BE, Sergeev Y, Smith J, Rubin B, Meallet MA, Forster RK, Hejtmancik JF, Schorderet DF; ''Mutations in PIP5K3 are associated with François-Neetens mouchetée fleck corneal dystrophy.''; Am J Hum Genet, 2005 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
112223view06:26, 2 October 2020EgonwRemoved the prefixes. We don't have support for that yet.
112200view14:27, 1 October 2020DeSlOntology Term : 'centronuclear myopathy' added !
112199view14:27, 1 October 2020DeSlOntology Term : 'Fleck corneal dystrophy' added !
112198view14:26, 1 October 2020DeSlOntology Term : 'Charcot-Marie-Tooth disease type 4B1' added !
112197view14:23, 1 October 2020DeSlAdded 3 rare (metabolic) diseases.
112196view14:15, 1 October 2020DeSlAdded effector functions for each metabolite.
112195view14:12, 1 October 2020DeSlAdded localization for metabolites as comment.
112180view09:24, 1 October 2020DeSlOntology Term : 'oculocerebrorenal syndrome' added !
112179view09:23, 1 October 2020DeSlAdded IDs for proteins under Phospholipase C
112177view09:17, 1 October 2020DeSlConnected last unconnected lines.
112176view09:15, 1 October 2020DeSlUpdated description
112175view09:14, 1 October 2020DeSlAdded last details
112174view08:52, 1 October 2020DeSlAdded PI-3 kinase III class.
112169view10:20, 30 September 2020DeSlAdded PI-3 kinase I + II.
112168view10:06, 30 September 2020DeSlAdded MTMRs section
112167view08:26, 30 September 2020DeSlUpdated IDs+interactions for PtdIns + PtdIns(3)P; reverted colour scheme to normal.
112150view12:38, 29 September 2020DeSlAdded ref for SHIP further reading material.
112149view12:37, 29 September 2020DeSlUpdated interaction for PIP5 kinase and SHIP.
112148view12:28, 29 September 2020DeSlUpdated IDs for PtdIns(3,4)P2.
112147view12:19, 29 September 2020DeSlUpdated description with refs.
112146view12:15, 29 September 2020DeSlUpdated description.
112145view12:11, 29 September 2020DeSlNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
4-phosphataseProtein3.1.3.78 (Enzyme Nomenclature) From [https://www.qmul.ac.uk/sbcs/iubmb/enzyme/EC3/1/3/78.html and https://enzyme.expasy.org/EC/3.1.3.78] :"Two pathways exist in mammalian cells to degrade 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate [PtdIns(4,5)P2] [2]. One is catalysed by this enzyme... The enzyme from human is specific for PtdIns(4,5)P2 as substrate, as it cannot use PtdIns(3,4,5)P3, PtdIns(3,4)P2, PtdIns(3,5)P2, PtdIns5P, PtdIns4P or PtdIns3P [2].In humans, the enzyme is localized to late endosomal/lysosomal membranes [2]." [2]: [PMID: 16365287]
ADPMetaboliteCHEBI:456216 (ChEBI)
ATPMetaboliteCHEBI:30616 (ChEBI)
DAGMetaboliteCHEBI:17815 (ChEBI) Diacylglycerol
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
Ins(1,4,5)P3MetaboliteCHEBI:203600 (ChEBI) phosphorylated on position 1,4 and 5.
MTM1ProteinQ13496 (Uniprot-TrEMBL) aka Myotubularin; gene name given in Fig. 1 of [PMID:16554828].
MTMR10ProteinQ9NXD2 (Uniprot-TrEMBL)
MTMR11ProteinA4FU01 (Uniprot-TrEMBL)
MTMR12ProteinQ9C0I1 (Uniprot-TrEMBL)
MTMR1ProteinQ13613 (Uniprot-TrEMBL)
MTMR2ProteinQ13614 (Uniprot-TrEMBL)
MTMR3ProteinQ13615 (Uniprot-TrEMBL)
MTMR4ProteinQ9NYA4 (Uniprot-TrEMBL)
MTMR6ProteinQ9Y217 (Uniprot-TrEMBL)
MTMR7ProteinQ9Y216 (Uniprot-TrEMBL)
MTMR8ProteinQ96EF0 (Uniprot-TrEMBL)
MTMR9ProteinQ96QG7 (Uniprot-TrEMBL)
OCRLProteinQ01968 (Uniprot-TrEMBL)
PI-3 kinase IProtein2.7.1.137 (Enzyme Nomenclature)
PI-3 kinase IIProtein2.7.1.154 (Enzyme Nomenclature) See also https://en.wikipedia.org/wiki/Class_II_PI_3-kinases
PI-3 kinase IIIProtein2.7.1.137 (Enzyme Nomenclature)
PI3K-C2αProteinO00443 (Uniprot-TrEMBL)
PI3K-C2βProteinO00750 (Uniprot-TrEMBL)
PI3K-C2γProteinO75747 (Uniprot-TrEMBL)
PIK3C3ProteinQ8NEB9 (Uniprot-TrEMBL)
PIK3CAProteinP42336 (Uniprot-TrEMBL)
PIK3CBProteinP42338 (Uniprot-TrEMBL)
PIK3CDProteinO00329 (Uniprot-TrEMBL)
PIK3CGProteinP48736 (Uniprot-TrEMBL)
PIK3R4ProteinQ99570 (Uniprot-TrEMBL)
PIKfyveProteinQ9Y2I7 (Uniprot-TrEMBL)
PIP-4 kinaseProtein2.7.1.149 (Enzyme Nomenclature) According to Rhea, this is the EC class.
PIP-5 kinase alphaProteinQ99755 (Uniprot-TrEMBL)
PIP-5 kinase betaProteinO14986 (Uniprot-TrEMBL)
PIP-5 kinase gammaProteinO60331 (Uniprot-TrEMBL) "PIP5Kγ, has three splicing variance; PIP5Kγ635, PIP5γ661, and PIP5Kγ687, making it one of the key regulators for producing PI(4,5)P2" [https://en.wikipedia.org/wiki/Phosphatidylinositol-4-phosphate_5-_kinases_(PIP5K)_in_neuronal_development]
PIP4K2AProteinP48426 (Uniprot-TrEMBL)
PIP4K2BProteinP78356 (Uniprot-TrEMBL)
PIP4K2CProteinQ8TBX8 (Uniprot-TrEMBL)
PIP4P1ProteinQ86T03 (Uniprot-TrEMBL)
PIP4P2ProteinQ8N4L2 (Uniprot-TrEMBL)
PLCB1ProteinQ9NQ66 (Uniprot-TrEMBL)
PLCB2ProteinQ00722 (Uniprot-TrEMBL)
PLCB3ProteinQ01970 (Uniprot-TrEMBL)
PLCB4ProteinQ15147 (Uniprot-TrEMBL)
PLCD1ProteinP51178 (Uniprot-TrEMBL)
PLCD3ProteinQ8N3E9 (Uniprot-TrEMBL)
PLCD4ProteinQ9BRC7 (Uniprot-TrEMBL)
PLCE1ProteinQ9P212 (Uniprot-TrEMBL)
PLCG1ProteinP19174 (Uniprot-TrEMBL)
PLCG2ProteinP16885 (Uniprot-TrEMBL)
PLCH1ProteinQ4KWH8 (Uniprot-TrEMBL)
PLCH2ProteinO75038 (Uniprot-TrEMBL)
PLCZ1ProteinQ86YW0 (Uniprot-TrEMBL)
PTENProteinP60484 (Uniprot-TrEMBL)
PhosphateMetaboliteCHEBI:43474 (ChEBI)
Phospholipase CProtein3.1.4.11 (Enzyme Nomenclature)
PtdIns(3)PMetaboliteCHEBI:58088 (ChEBI)
  • phosphorylated on position 1 and 3; position 1 connected to DAG.
  • Localization: Endosomes
  • Function: Endocytic membrane traffic, autophagy, phagosome maturation
PtdIns(3,4)P2MetaboliteCHEBI:57658 (ChEBI)
  • phosphorylated on position 1, 3 and 4; position 1 connected to DAG.
  • Localization: Plasma membrane
  • Function: Signaling, phagocyte oxidase, cytoskeletal dynamics
PtdIns(3,4,5)P3MetaboliteCHEBI:57836 (ChEBI)
  • phosphorylated on position 1, 3, 4 and 5; position 1 connected to DAG.
  • Localization: Plasma membrane
  • Function: Signaling, cytoskeletal dynamics
PtdIns(3,5)P2MetaboliteCHEBI:57923 (ChEBI)
  • phosphorylated on position 1, 3 and 5; position 1 connected to DAG.
  • Localization: Endosomes
  • Function: Osmotic stress responses, signaling, vacuole homeostasis
PtdIns(4)PMetaboliteCHEBI:58178 (ChEBI)
  • phosphorylated on position 1 and 4; position 1 connected to DAG.
  • Localization: Golgi
  • Function: Golgi-to-PM traffic
PtdIns(4,5)P2MetaboliteCHEBI:58456 (ChEBI)
  • phosphatidylinositol 4,5-bisphosphate
  • Localization: Plasma membrane, Nucleus
  • Function: Endocytosis, cytoskeletal dynamics
PtdIns(5)PMetaboliteCHEBI:57795 (ChEBI)
  • aka phosphatidylinositol 5-phosphate
  • phosphorylated on position 1 and 5; position 1 connected to DAG.
  • Localization: Nucleus
  • Function: Apoptosis
PtdInsMetaboliteCHEBI:57880 (ChEBI) phosphorylated on position 1; position 1 connected to DAG.
SACM1LProteinQ9NTJ5 (Uniprot-TrEMBL) Annotation based on Uniprot " Can also catalyze the hydrolysis of phosphatidylinositol 3-phosphate (PtdIns3P)" and EC.3.1.3.64
SBF1ProteinO95248 (Uniprot-TrEMBL) aka Myotubularin-related protein 5
SBF2ProteinQ86WG5 (Uniprot-TrEMBL) aka Myotubularin-related protein 13
SHIP (1)ProteinQ92835 (Uniprot-TrEMBL) EC:3.1.3.86. Annotated based on caption of Fig. 1 [PMID:16554828] and "Src homology 2 (SH2) domain containing inositol polyphosphate 5-phosphatase 1 (SHIP1)" [https://en.wikipedia.org/wiki/INPP5D]

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
DAGmim-conversion33180 (Rhea)
PtdIns(3)PPtdIns(3,4)P2mim-conversion17195 (Rhea)
PtdIns(3)PPtdIns(3,5)P2mim-conversion13610 (Rhea)
PtdIns(3)PPtdInsmim-conversion12317 (Rhea)
PtdIns(3,4)P2PtdIns(3)Pmim-conversion17194 (Rhea)
PtdIns(3,4)P2PtdIns(3,4,5)P3mim-conversion25530 (Rhea)
PtdIns(3,4)P2PtdIns(4)Pmim-conversion18374 (Rhea) "PTEN protein acts as a phosphatase to dephosphorylate phosphatidylinositol (3,4,5)-trisphosphate (PtdIns (3,4,5)P3 or PIP3)." [https://en.wikipedia.org/wiki/PTEN_(gene)]
PtdIns(3,4,5)P3PtdIns(3,4)P2mim-conversion25529 (Rhea)
PtdIns(3,4,5)P3PtdIns(4,5)P2mim-conversion21294 (Rhea)
PtdIns(4)PPtdIns(3,4)P2mim-conversion18375 (Rhea)
PtdIns(4)PPtdIns(4,5)P2mim-conversion14427 (Rhea)
PtdIns(4)PPtdInsmim-conversion55653 (Rhea)
PtdIns(4,5)P2Ins(1,4,5)P3mim-conversion33180 (Rhea)
PtdIns(4,5)P2PtdIns(3,4,5)P3mim-conversion21293 (Rhea)
PtdIns(4,5)P2PtdIns(4)Pmim-conversion14426 (Rhea)
PtdIns(4,5)P2PtdIns(5)Pmim-conversion12282 (Rhea)
PtdIns(5)PPtdIns(4,5)P2mim-conversion12281 (Rhea) The addition of a third phosphate to obtain PtdIns(4,5)P2 can be performed by two enzymes, which either add the phosphate at the D4 or D5 position in the inositol ring. This last phosphorylation step is depending on where the second phosphphate is located (D5 or D4 repectively). Rephrased from [PMID: 9367159]: "The type I enzyme PIP-4-kinase phosphorylates PtdIns-4-P at the D-5 position (of the inositol ring).The type II enzyme however ( abundant in some tissues), phosphorylates PtdIns-5-P at the D-4 position, and thus should be considered as a 4-OH kinase, or PIP(4)K."
PtdInsPtdIns(3)Pmim-conversion12318 (Rhea)
PtdInsPtdIns(3)Pmim-conversion12710 (Rhea)
PtdInsPtdIns(4)Pmim-conversion55654 (Rhea)
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