PIP4K2A

{{short description|Kinase enzyme}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox_gene}} '''Phosphatidylinositol-5-phosphate 4-kinase type-2 alpha''' is an enzyme that in humans is encoded by the ''PIP4K2A'' gene.<ref name="pmid7852364">{{cite journal | vauthors = Boronenkov IV, Anderson RA | title = The sequence of phosphatidylinositol-4-phosphate 5-kinase defines a novel family of lipid kinases | journal = The Journal of Biological Chemistry | volume = 270 | issue = 7 | pages = 2881–2884 | date = February 1995 | pmid = 7852364 | doi = 10.1074/jbc.270.7.2881 | doi-access = free }}</ref><ref name="pmid9367159">{{cite journal | vauthors = Rameh LE, Tolias KF, Duckworth BC, Cantley LC | title = A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate | journal = Nature | volume = 390 | issue = 6656 | pages = 192–196 | date = November 1997 | pmid = 9367159 | doi = 10.1038/36621 | s2cid = 4403301 | bibcode = 1997Natur.390..192R }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: PIP5K2A phosphatidylinositol-4-phosphate 5-kinase, type II, alpha| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=5305}}</ref>

== Function ==

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.<ref name="entrez" />

==Clinical significance== 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 i<nowiki/>n ethnically diverse populations.<ref>{{cite journal | vauthors = Xu H, Yang W, Perez-Andreu V, Devidas M, Fan Y, Cheng C, Pei D, Scheet P, Burchard EG, Eng C, Huntsman S, Torgerson DG, Dean M, Winick NJ, Martin PL, Camitta BM, Bowman WP, Willman CL, Carroll WL, Mullighan CG, Bhojwani D, Hunger SP, Pui CH, Evans WE, Relling MV, Loh ML, Yang JJ | title = Novel susceptibility variants at 10p12.31-12.2 for childhood acute lymphoblastic leukemia in ethnically diverse populations | journal = Journal of the National Cancer Institute | volume = 105 | issue = 10 | pages = 733–742 | date = May 2013 | pmid = 23512250 | pmc = 3691938 | doi = 10.1093/jnci/djt042 }}</ref><ref>{{cite journal | vauthors = Liao F, Yin D, Zhang Y, Hou Q, Zheng Z, Yang L, Shu Y, Xu H, Li Y | title = Association Between PIP4K2A Polymorphisms and Acute Lymphoblastic Leukemia Susceptibility | journal = Medicine | volume = 95 | issue = 18 | article-number = e3542 | date = May 2016 | pmid = 27149463 | pmc = 4863780 | doi = 10.1097/MD.0000000000003542 }}</ref>

== PIP4K2A Inhibitors == THZ-P1-2<ref>{{cite journal | vauthors = 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 | title = Targeting the PI5P4K Lipid Kinase Family in Cancer Using Covalent Inhibitors | journal = Cell Chemical Biology | volume = 27 | issue = 5 | pages = 525–537.e6 | date = May 2020 | pmid = 32130941 | pmc = 7286548 | doi = 10.1016/j.chembiol.2020.02.003 }}</ref> (covalent inhibitor) as well as BAY-091 and BAY-297<ref>{{cite journal | vauthors = 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 | title = Discovery and Characterization of the Potent and Highly Selective 1,7-Naphthyridine-Based Inhibitors BAY-091 and BAY-297 of the Kinase PIP4K2A | journal = Journal of Medicinal Chemistry | volume = 64 | issue = 21 | pages = 15883–15911 | date = November 2021 | pmid = 34699202 | doi = 10.1021/acs.jmedchem.1c01245 | s2cid = 240000214 | doi-access = free }}</ref> (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.<ref>{{Cite web |title=Donated Chemical Probes |date=12 June 2018 |url=https://www.thesgc.org/donated-chemical-probes |access-date=July 31, 2023}}</ref>

== References == {{reflist}}

== Further reading == {{refbegin | 2}} * {{cite journal | vauthors = Loijens JC, Boronenkov IV, Parker GJ, Anderson RA | title = The phosphatidylinositol 4-phosphate 5-kinase family | journal = Advances in Enzyme Regulation | volume = 36 | pages = 115–140 | year = 1996 | pmid = 8869744 | doi = 10.1016/0065-2571(95)00005-4 }} * {{cite journal | vauthors = Niiro H, Clark EA | title = Branches of the B cell antigen receptor pathway are directed by protein conduits Bam32 and Carma1 | journal = Immunity | volume = 19 | issue = 5 | pages = 637–640 | date = November 2003 | pmid = 14614850 | doi = 10.1016/S1074-7613(03)00303-0 | doi-access = free }} * {{cite journal | vauthors = Carpenter CL | title = Btk-dependent regulation of phosphoinositide synthesis | journal = Biochemical Society Transactions | volume = 32 | issue = Pt 2 | pages = 326–329 | date = April 2004 | pmid = 15046600 | doi = 10.1042/BST0320326 }} * {{cite journal | vauthors = Tolias KF, Cantley LC, Carpenter CL | title = Rho family GTPases bind to phosphoinositide kinases | journal = The Journal of Biological Chemistry | volume = 270 | issue = 30 | pages = 17656–17659 | date = July 1995 | pmid = 7629060 | doi = 10.1074/jbc.270.30.17656 | doi-access = free }} * {{cite journal | vauthors = Divecha N, Truong O, Hsuan JJ, Hinchliffe KA, Irvine RF | title = The cloning and sequence of the C isoform of PtdIns4P 5-kinase | journal = The Biochemical Journal | volume = 309 | issue = 3 | pages = 715–9 | date = August 1995 | pmid = 7639683 | pmc = 1135690 | doi = 10.1042/bj3090715}} * {{cite journal | vauthors = Rozenvayn N, Flaumenhaft R | title = Protein kinase C mediates translocation of type II phosphatidylinositol 5-phosphate 4-kinase required for platelet alpha-granule secretion | journal = The Journal of Biological Chemistry | volume = 278 | issue = 10 | pages = 8126–34 | date = March 2003 | pmid = 12509423 | doi = 10.1074/jbc.M206493200 | doi-access = free }} * {{cite journal | vauthors = Saito K, Tolias KF, Saci A, Koon HB, Humphries LA, Scharenberg A, Rawlings DJ, Kinet JP, Carpenter CL | title = BTK regulates PtdIns-4,5-P2 synthesis: importance for calcium signaling and PI3K activity | journal = Immunity | volume = 19 | issue = 5 | pages = 669–678 | date = November 2003 | pmid = 14614854 | doi = 10.1016/S1074-7613(03)00297-8 | doi-access = free }} * {{cite journal | vauthors = 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 | title = Evidence for association of DNA sequence variants in the phosphatidylinositol-4-phosphate 5-kinase IIalpha gene (PIP5K2A) with schizophrenia | journal = Molecular Psychiatry | volume = 11 | issue = 9 | pages = 837–846 | date = September 2006 | pmid = 16801950 | doi = 10.1038/sj.mp.4001864 | doi-access = free }} * {{cite journal | vauthors = Bakker SC, Hoogendoorn ML, Hendriks J, Verzijlbergen K, Caron S, Verduijn W, Selten JP, Pearson PL, Kahn RS, Sinke RJ | title = The PIP5K2A and RGS4 genes are differentially associated with deficit and non-deficit schizophrenia | journal = Genes, Brain and Behavior | volume = 6 | issue = 2 | pages = 113–119 | date = March 2007 | pmid = 17410640 | doi = 10.1111/j.1601-183X.2006.00234.x | s2cid = 32120485 }} * {{cite journal | vauthors = He Z, Li Z, Shi Y, Tang W, Huang K, Ma G, Zhou J, Meng J, Li H, Feng G, He L | title = The PIP5K2A gene and schizophrenia in the Chinese population--a case-control study | journal = Schizophrenia Research | volume = 94 | issue = 1-3 | pages = 359–365 | date = August 2007 | pmid = 17555944 | doi = 10.1016/j.schres.2007.04.013 | s2cid = 34716299 }} {{refend}}

== External links == * {{PDBe-KB2|P48426|Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha}}