Phosphoinositides metabolism (WP4971)
Homo sapiens
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 [https://doi.org/10.1038/nmeth867 Rusten et al], annotated with biochemical interaction database [https://www.rhea-db.org/ Rhea], and diseases (depicted in pink) with corresponding [https://www.omim.org/ OMIM-identifiers.]. Dashed lines depict proposed interactions which have not been characterised (yet)
Authors
Denise Slenter , Egon Willighagen , and Elisa SantarsieroCited In
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Organism
Homo sapiensCommunities
Inborn Errors of Metabolism (IEM) Pathways Lipids and LIPID MAPS Rare DiseasesAnnotations
Disease Ontology: oculocerebrorenal syndrome Charcot-Marie-Tooth disease type 4B1 Fleck corneal dystrophy centronuclear myopathy
Pathway Ontology: phosphatidylinositol metabolic pathway
Participants
| Label | Type | Compact Identifier | Comment |
|---|---|---|---|
| PtdIns(5)P | Metabolite | chebi:57795 | aka phosphatidylinositol 5-phosphatephosphorylated on position 1 and 5; position 1 connected to DAG.Localization: NucleusFunction: Apoptosis |
| DAG | Metabolite | chebi:17815 | Diacylglycerol |
| ATP | Metabolite | chebi:30616 | |
| H2O | Metabolite | chebi:15377 | |
| Phosphate | Metabolite | chebi:43474 | |
| PtdIns(4,5)P2 | Metabolite | chebi:58456 | phosphatidylinositol 4,5-bisphosphateLocalization: Plasma membrane, NucleusFunction: Endocytosis, cytoskeletal dynamics |
| PtdIns(3,5)P2 | Metabolite | chebi:57923 | phosphorylated on position 1, 3 and 5; position 1 connected to DAG.Localization: EndosomesFunction: Osmotic stress responses, signaling, vacuole homeostasis |
| PtdIns | Metabolite | chebi:57880 | phosphorylated on position 1; position 1 connected to DAG. |
| PtdIns(3)P | Metabolite | chebi:58088 | phosphorylated on position 1 and 3; position 1 connected to DAG.Localization: EndosomesFunction: Endocytic membrane traffic, autophagy, phagosome maturation |
| PtdIns(3,4)P2 | Metabolite | chebi:57658 | phosphorylated on position 1, 3 and 4; position 1 connected to DAG.Localization: Plasma membraneFunction: Signaling, phagocyte oxidase, cytoskeletal dynamics |
| PtdIns(4)P | Metabolite | chebi:58178 | phosphorylated on position 1 and 4; position 1 connected to DAG.Localization: GolgiFunction: Golgi-to-PM traffic |
| PtdIns(3,4,5)P3 | Metabolite | chebi:57836 | phosphorylated on position 1, 3, 4 and 5; position 1 connected to DAG.Localization: Plasma membraneFunction: Signaling, cytoskeletal dynamics |
| Ins(1,4,5)P3 | Metabolite | chebi:203600 | phosphorylated on position 1,4 and 5. |
| ADP | Metabolite | chebi:456216 | |
| H+ | Metabolite | chebi:15378 | |
| PI-3 kinase III | Protein | eccode:2.7.1.137 | |
| PIP-5 kinase alpha | Protein | uniprot:Q99755 | |
| 4-phosphatase | Protein | eccode:3.1.3.78 | 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] |
| PTEN | Protein | uniprot:P60484 | |
| SACM1L | Protein | uniprot:Q9NTJ5 | Annotation based on Uniprot ' Can also catalyze the hydrolysis of phosphatidylinositol 3-phosphate (PtdIns3P)' and EC.3.1.3.64 |
| PIP-4 kinase | Protein | eccode:2.7.1.149 | According to Rhea, this is the EC class. |
| PLCB2 | Protein | uniprot:Q00722 | |
| MTMR1 | Protein | uniprot:Q13613 | |
| PIKfyve | Protein | uniprot:Q9Y2I7 | |
| PLCH1 | Protein | uniprot:Q4KWH8 | |
| PI3K-C2α | Protein | uniprot:O00443 | |
| PTEN | Protein | uniprot:P60484 | |
| PLCG1 | Protein | uniprot:P19174 | |
| MTM1 | Protein | uniprot:Q13496 | aka Myotubularin; gene name given in Fig. 1 of [PMID:16554828]. |
| OCRL | Protein | uniprot:Q01968 | |
| PLCB1 | Protein | uniprot:Q9NQ66 | |
| PIK3CG | Protein | uniprot:P48736 | |
| PI-3 kinase I | Protein | eccode:2.7.1.137 | |
| PIP4P1 | Protein | uniprot:Q86T03 | |
| SHIP (1) | Protein | uniprot:Q92835 | 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] |
| PIP-5 kinase gamma | Protein | uniprot:O60331 | '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] |
| PIP4K2A | Protein | uniprot:P48426 | |
| PIP4K2C | Protein | uniprot:Q8TBX8 | |
| PIP4K2B | Protein | uniprot:P78356 | |
| PIP4P2 | Protein | uniprot:Q8N4L2 | |
| PIP-5 kinase beta | Protein | uniprot:O14986 | |
| PIK3CB | Protein | uniprot:P42338 | |
| PIK3CA | Protein | uniprot:P42336 | |
| PIK3CD | Protein | uniprot:O00329 | |
| Phospholipase C | Protein | eccode:3.1.4.11 | |
| PLCB3 | Protein | uniprot:Q01970 | |
| PLCB4 | Protein | uniprot:Q15147 | |
| PLCG2 | Protein | uniprot:P16885 | |
| PLCE1 | Protein | uniprot:Q9P212 | |
| PLCD1 | Protein | uniprot:P51178 | |
| PLCD3 | Protein | uniprot:Q8N3E9 | |
| PLCD4 | Protein | uniprot:Q9BRC7 | |
| PLCH2 | Protein | uniprot:O75038 | |
| PLCZ1 | Protein | uniprot:Q86YW0 | |
| PIK3CG | Protein | uniprot:P48736 | |
| PI-3 kinase I | Protein | eccode:2.7.1.137 | |
| PIK3CB | Protein | uniprot:P42338 | |
| PIK3CA | Protein | uniprot:P42336 | |
| PIK3CD | Protein | uniprot:O00329 | |
| PIP-5 kinase alpha | Protein | uniprot:Q99755 | |
| PIP-5 kinase gamma | Protein | uniprot:O60331 | '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] |
| PIP-5 kinase beta | Protein | uniprot:O14986 | |
| 4-phosphatase | Protein | eccode:3.1.3.78 | 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] |
| PIP4P1 | Protein | uniprot:Q86T03 | |
| PIP4P2 | Protein | uniprot:Q8N4L2 | |
| PIP-4 kinase | Protein | eccode:2.7.1.149 | According to Rhea, this is the EC class. |
| PIP4K2A | Protein | uniprot:P48426 | |
| PIP4K2C | Protein | uniprot:Q8TBX8 | |
| PIP4K2B | Protein | uniprot:P78356 | |
| MTMR10 | Protein | uniprot:Q9NXD2 | |
| MTMR11 | Protein | uniprot:A4FU01 | |
| MTMR12 | Protein | uniprot:Q9C0I1 | |
| MTMR2 | Protein | uniprot:Q13614 | |
| MTMR3 | Protein | uniprot:Q13615 | |
| MTMR4 | Protein | uniprot:Q9NYA4 | |
| MTMR6 | Protein | uniprot:Q9Y217 | |
| MTMR7 | Protein | uniprot:Q9Y216 | |
| MTMR8 | Protein | uniprot:Q96EF0 | |
| MTMR9 | Protein | uniprot:Q96QG7 | |
| SBF2 | Protein | uniprot:Q86WG5 | aka Myotubularin-related protein 13 |
| SBF1 | Protein | uniprot:O95248 | aka Myotubularin-related protein 5 |
| PIK3CG | Protein | uniprot:P48736 | |
| PI-3 kinase I | Protein | eccode:2.7.1.137 | |
| PIK3CB | Protein | uniprot:P42338 | |
| PIK3CA | Protein | uniprot:P42336 | |
| PIK3CD | Protein | uniprot:O00329 | |
| PI-3 kinase II | Protein | eccode:2.7.1.154 | See also https://en.wikipedia.org/wiki/Class_II_PI_3-kinases |
| PI3K-C2β | Protein | uniprot:O00750 | |
| PI3K-C2γ | Protein | uniprot:O75747 | |
| PIK3C3 | Protein | uniprot:Q8NEB9 | |
| PIK3R4 | Protein | uniprot:Q99570 | |
| MTM1 | Protein | uniprot:Q13496 | aka Myotubularin; gene name given in Fig. 1 of [PMID:16554828]. |
References
- Laporte J, Hu LJ, Kretz C, Mandel JL, Kioschis P, Coy JF, et al. A gene mutated in X-linked myotubular myopathy defines a new putative tyrosine phosphatase family conserved in yeast. Nat Genet. 1996 Jun;13(2):175–82. PubMed Europe PMC Scholia
- Rameh LE, Tolias KF, Duckworth BC, Cantley LC. A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate. Nature. 1997 Nov 13;390(6656):192–6. PubMed Europe PMC Scholia
- Rohrschneider LR, Fuller JF, Wolf I, Liu Y, Lucas DM. Structure, function, and biology of SHIP proteins. Genes Dev. 2000 Mar 1;14(5):505–20. PubMed Europe PMC Scholia
- Bolino A, Muglia M, Conforti FL, LeGuern E, Salih MA, Georgiou DM, et al. Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nat Genet. 2000 May;25(1):17–9. PubMed Europe PMC Scholia
- Li S, Tiab L, Jiao X, Munier FL, Zografos L, Frueh BE, et al. Mutations in PIP5K3 are associated with François-Neetens mouchetée fleck corneal dystrophy. Am J Hum Genet. 2005 Jul;77(1):54–63. PubMed Europe PMC Scholia
- Ungewickell A, Hugge C, Kisseleva M, Chang S-C, Zou J, Feng Y, et al. The identification and characterization of two phosphatidylinositol-4,5-bisphosphate 4-phosphatases. Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):18854–9. PubMed Europe PMC Scholia
- Rusten TE, Stenmark H. Analyzing phosphoinositides and their interacting proteins. Nat Methods. 2006 Apr;3(4):251–8. PubMed Europe PMC Scholia
- Backer JM. The regulation and function of Class III PI3Ks: novel roles for Vps34. Biochem J. 2008 Feb 15;410(1):1–17. PubMed Europe PMC Scholia
- Malek M, Kielkowska A, Chessa T, Anderson KE, Barneda D, Pir P, et al. PTEN Regulates PI(3,4)P2 Signaling Downstream of Class I PI3K. Mol Cell. 2017 Nov 2;68(3):566-580.e10. PubMed Europe PMC Scholia