Phosphatidylinositol-5-phosphate 4-kinase type-2 alpha is an enzyme that in humans is encoded by the PIP4K2A gene.[5][6][7]
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Phosphatidylinositol-4,5-bisphosphate, the precursor to second messengers of the phosphoinositide signal transduction pathways, is thought to be involved in the regulation of secretion, cell proliferation, differentiation, and motility. The protein encoded by this gene is one of a family of enzymes capable of catalyzing the phosphorylation of phosphatidylinositol-4-phosphate on the fifth hydroxyl of the myo-inositol ring to form phosphatidylinositol-4,5-bisphosphate.
The amino acid sequence of this enzyme does not show homology to other kinases, but the recombinant protein does exhibit kinase activity. This gene is a member of the phosphatidylinositol-4-phosphate 5-kinase family.[7]
Through genome wide association studies (GWAS), some of the single nucleotide polymorphisms (SNPs) located in this gene have been noticed to be significantly associated with susceptibility of childhood acute lymphoblastic leukaemia in ethnically diverse populations.[8][9]
THZ-P1-2[10] (covalent inhibitor) as well as BAY-091 and BAY-297[11] (reversible inhibitors) have been reported as potent and selective PIP4K2A inhibitors. BAY-091 fulfills the quality criteria for a 'Donated Chemical Probe' as defined by the Structural Genomics Consortium.[12]
Sivakumaren SC, Shim H, Zhang T, Ferguson FM, Lundquist MR, Browne CM, Seo HS, Paddock MN, Manz TD, Jiang B, Hao MF, Krishnan P, Wang DG, Yang TJ, Kwiatkowski NP, Ficarro SB, Cunningham JM, Marto JA, Dhe-Paganon S, Cantley LC, Gray NS (2020). "Targeting the PI5P4K Lipid Kinase Family in Cancer Using Covalent Inhibitors". Cell Chemical Biology. 27 (5): 525–537.e6. doi:10.1016/j.chembiol.2020.02.003. PMC 7286548. PMID 32130941. Wortmann L, Bräuer N, Holton SJ, Irlbacher H, Weiske J, Lechner C, Meier R, Karén J, Siöberg CB, Pütter V, Christ CD, Ter Laak A, Lienau P, Lesche R, Nicke B, Cheung SH, Bauser M, Haegebarth A, von Nussbaum F, Mumberg D, Lemos C (2021). "Discovery and Characterization of the Potent and Highly Selective 1,7-Naphthyridine-Based Inhibitors BAY-091 and BAY-297 of the Kinase PIP4K2A". Journal of Medicinal Chemistry. 64 (21): 15883–15911. doi:10.1021/acs.jmedchem.1c01245. PMID 34699202. S2CID 240000214.
- Loijens JC, Boronenkov IV, Parker GJ, Anderson RA (1996). "The phosphatidylinositol 4-phosphate 5-kinase family". Advances in Enzyme Regulation. 36: 115–40. doi:10.1016/0065-2571(95)00005-4. PMID 8869744.
- Niiro H, Clark EA (November 2003). "Branches of the B cell antigen receptor pathway are directed by protein conduits Bam32 and Carma1". Immunity. 19 (5): 637–40. doi:10.1016/S1074-7613(03)00303-0. PMID 14614850.
- Carpenter CL (April 2004). "Btk-dependent regulation of phosphoinositide synthesis". Biochemical Society Transactions. 32 (Pt 2): 326–9. doi:10.1042/BST0320326. PMID 15046600.
- Tolias KF, Cantley LC, Carpenter CL (July 1995). "Rho family GTPases bind to phosphoinositide kinases". The Journal of Biological Chemistry. 270 (30): 17656–9. doi:10.1074/jbc.270.30.17656. PMID 7629060.
- Divecha N, Truong O, Hsuan JJ, Hinchliffe KA, Irvine RF (August 1995). "The cloning and sequence of the C isoform of PtdIns4P 5-kinase". The Biochemical Journal. 309 (3): 715–9. doi:10.1042/bj3090715. PMC 1135690. PMID 7639683.
- Rozenvayn N, Flaumenhaft R (March 2003). "Protein kinase C mediates translocation of type II phosphatidylinositol 5-phosphate 4-kinase required for platelet alpha-granule secretion". The Journal of Biological Chemistry. 278 (10): 8126–34. doi:10.1074/jbc.M206493200. PMID 12509423.
- Saito K, Tolias KF, Saci A, Koon HB, Humphries LA, Scharenberg A, Rawlings DJ, Kinet JP, Carpenter CL (November 2003). "BTK regulates PtdIns-4,5-P2 synthesis: importance for calcium signaling and PI3K activity". Immunity. 19 (5): 669–78. doi:10.1016/S1074-7613(03)00297-8. PMID 14614854.
- Schwab SG, Knapp M, Sklar P, Eckstein GN, Sewekow C, Borrmann-Hassenbach M, Albus M, Becker T, Hallmayer JF, Lerer B, Maier W, Wildenauer DB (September 2006). "Evidence for association of DNA sequence variants in the phosphatidylinositol-4-phosphate 5-kinase IIalpha gene (PIP5K2A) with schizophrenia". Molecular Psychiatry. 11 (9): 837–46. doi:10.1038/sj.mp.4001864. PMID 16801950.
- Bakker SC, Hoogendoorn ML, Hendriks J, Verzijlbergen K, Caron S, Verduijn W, Selten JP, Pearson PL, Kahn RS, Sinke RJ (March 2007). "The PIP5K2A and RGS4 genes are differentially associated with deficit and non-deficit schizophrenia". Genes, Brain and Behavior. 6 (2): 113–9. doi:10.1111/j.1601-183X.2006.00234.x. PMID 17410640. S2CID 32120485.
- He Z, Li Z, Shi Y, Tang W, Huang K, Ma G, Zhou J, Meng J, Li H, Feng G, He L (August 2007). "The PIP5K2A gene and schizophrenia in the Chinese population--a case-control study". Schizophrenia Research. 94 (1–3): 359–65. doi:10.1016/j.schres.2007.04.013. PMID 17555944. S2CID 34716299.
- Overview of all the structural information available in the PDB for UniProt: P48426 (Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha) at the PDBe-KB.