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) c9f aka phosphatidylinositol 5-phosphate phosphorylated on position 1 and 5; position 1 connected to DAG. Localization: Nucleus Function: Apoptosis Diacylglycerol 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] b64 a01 Annotation based on Uniprot " Can also catalyze the hydrolysis of phosphatidylinositol 3-phosphate (PtdIns3P)" and EC.3.1.3.64 According to Rhea, this is the EC class. aka Myotubularin; gene name given in Fig. 1 of [PMID:16554828]. phosphatidylinositol 4,5-bisphosphate Localization: Plasma membrane, Nucleus Function: Endocytosis, cytoskeletal dynamics 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] a0c "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] phosphorylated on position 1, 3 and 5; position 1 connected to DAG. Localization: Endosomes Function: Osmotic stress responses, signaling, vacuole homeostasis phosphorylated on position 1; position 1 connected to DAG. phosphorylated on position 1 and 3; position 1 connected to DAG. Localization: Endosomes Function: Endocytic membrane traffic, autophagy, phagosome maturation phosphorylated on position 1, 3 and 4; position 1 connected to DAG. Localization: Plasma membrane Function: Signaling, phagocyte oxidase, cytoskeletal dynamics phosphorylated on position 1 and 4; position 1 connected to DAG. Localization: Golgi Function: Golgi-to-PM traffic phosphorylated on position 1, 3, 4 and 5; position 1 connected to DAG. Localization: Plasma membrane Function: Signaling, cytoskeletal dynamics phosphorylated on position 1,4 and 5. "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] 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] According to Rhea, this is the EC class. aka Myotubularin-related protein 13 aka Myotubularin-related protein 5 See also https://en.wikipedia.org/wiki/Class_II_PI_3-kinases dbb aka Myotubularin; gene name given in Fig. 1 of [PMID:16554828]. a01 a6d 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." a6d "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)] b64 More details on the complex (known for yeast) can be found on the COmplex portal: https://www.ebi.ac.uk/complexportal/complex/CPX-1881 oculocerebrorenal syndrome DOID:1056 Human Disease Ontology phosphatidylinositol metabolic pathway PW:0002417 Pathway Ontology Charcot-Marie-Tooth disease type 4B1 DOID:0110191 Human Disease Ontology Fleck corneal dystrophy DOID:0060448 Human Disease Ontology centronuclear myopathy DOID:14717 Human Disease Ontology 16554828 PubMed Analyzing phosphoinositides and their interacting proteins. Nat Methods 2006 Rusten TE Stenmark H 8640223 PubMed A gene mutated in X-linked myotubular myopathy definesa new putative tyrosine phosphatase family conserved in yeast. Nat Genet 1996 Laporte J Hu LJ Kretz C Mandel JL Kioschis P Coy JF Klauck SM Poustka A Dahl N 10802647 PubMed Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nat Genet 2000 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 15902656 PubMed Mutations in PIP5K3 are associated with François-Neetens mouchetée fleck corneal dystrophy. Am J Hum Genet 2005 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 16365287 PubMed The identification and characterization of two phosphatidylinositol-4,5-bisphosphate 4-phosphatases. Proc Natl Acad Sci U S A 2005 Ungewickell A Hugge C Kisseleva M Chang SC Zou J Feng Y Galyov EE Wilson M Majerus PW 29056325 PubMed PTEN Regulates PI(3,4)P<sub>2</sub>Signaling Downstream of Class I PI3K. Mol Cell 2017 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 10716940 PubMed Structure, function, and biology of SHIP proteins. Genes Dev 2000 Rohrschneider LR Fuller JF Wolf I Liu Y Lucas DM 18215151 PubMed The regulation and function of Class III PI3Ks:novel roles for Vps34. Biochem J 2008 Backer JM 9367159 PubMed A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate. Nature 1997 Rameh LE Tolias KF Duckworth BC Cantley LC