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)c9faka phosphatidylinositol 5-phosphatephosphorylated on position 1 and 5; position 1 connected to DAG.Localization: NucleusFunction: ApoptosisDiacylglycerolFrom [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]b64a01Annotation based on Uniprot " Can also catalyze the hydrolysis of phosphatidylinositol 3-phosphate (PtdIns3P)" and EC.3.1.3.64According to Rhea, this is the EC class.aka Myotubularin; gene name given in Fig. 1 of [PMID:16554828].phosphatidylinositol 4,5-bisphosphateLocalization: Plasma membrane, NucleusFunction: Endocytosis, cytoskeletal dynamicsEC: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: EndosomesFunction: Osmotic stress responses, signaling, vacuole homeostasisphosphorylated on position 1; position 1 connected to DAG.phosphorylated on position 1 and 3; position 1 connected to DAG.Localization: EndosomesFunction: Endocytic membrane traffic, autophagy, phagosome maturationphosphorylated on position 1, 3 and 4; position 1 connected to DAG.Localization: Plasma membraneFunction: Signaling, phagocyte oxidase, cytoskeletal dynamicsphosphorylated on position 1 and 4; position 1 connected to DAG.Localization: GolgiFunction: Golgi-to-PM trafficphosphorylated on position 1, 3, 4 and 5; position 1 connected to DAG.Localization: Plasma membraneFunction: Signaling, cytoskeletal dynamicsphosphorylated 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 13aka Myotubularin-related protein 5See also https://en.wikipedia.org/wiki/Class_II_PI_3-kinasesdbbaka Myotubularin; gene name given in Fig. 1 of [PMID:16554828].a01a6dThe 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)]b64More details on the complex (known for yeast) can be found on the COmplex portal: https://www.ebi.ac.uk/complexportal/complex/CPX-1881oculocerebrorenal syndromeDOID:1056Human Disease Ontologyphosphatidylinositol metabolic pathwayPW:0002417Pathway OntologyCharcot-Marie-Tooth disease type 4B1DOID:0110191Human Disease OntologyFleck corneal dystrophyDOID:0060448Human Disease Ontologycentronuclear myopathyDOID:14717Human Disease Ontology16554828PubMedAnalyzing phosphoinositides and their interacting proteins.Nat Methods2006Rusten TEStenmark H8640223PubMedA gene mutated in X-linked myotubular myopathy definesa new putative tyrosine phosphatase family conserved in yeast.Nat Genet1996Laporte JHu LJKretz CMandel JLKioschis PCoy JFKlauck SMPoustka ADahl N10802647PubMedCharcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2.Nat Genet2000Bolino AMuglia MConforti FLLeGuern ESalih MAGeorgiou DMChristodoulou KHausmanowa-Petrusewicz IMandich PSchenone AGambardella ABono FQuattrone ADevoto MMonaco AP15902656PubMedMutations in PIP5K3 are associated with François-Neetens mouchetée fleck corneal dystrophy.Am J Hum Genet2005Li STiab LJiao XMunier FLZografos LFrueh BESergeev YSmith JRubin BMeallet MAForster RKHejtmancik JFSchorderet DF16365287PubMedThe identification and characterization of two phosphatidylinositol-4,5-bisphosphate 4-phosphatases.Proc Natl Acad Sci U S A2005Ungewickell AHugge CKisseleva MChang SCZou JFeng YGalyov EEWilson MMajerus PW29056325PubMedPTEN Regulates PI(3,4)P<sub>2</sub>Signaling Downstream of Class I PI3K.Mol Cell2017Malek MKielkowska AChessa TAnderson KEBarneda DPir PNakanishi HEguchi SKoizumi ASasaki JJuvin VKiselev VYNiewczas IGray AValayer ASpensberger DImbert MFelisbino SHabuchi TBeinke SCosulich SLe Novère NSasaki TClark JHawkins PTStephens LR10716940PubMedStructure, function, and biology of SHIP proteins.Genes Dev2000Rohrschneider LRFuller JFWolf ILiu YLucas DM18215151PubMedThe regulation and function of Class III PI3Ks:novel roles for Vps34.Biochem J2008Backer JM9367159PubMedA new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate.Nature1997Rameh LETolias KFDuckworth BCCantley LC