Phosphatidylinositol-5-phosphate 4-kinase type-2 alpha is an enzyme that in humans is encoded by the PIP4K2A gene.[5][6][7]

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.[7]

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 in ethnically diverse populations.[8][9]

PIP4K2A Inhibitors

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]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000150867 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000026737 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Boronenkov IV, Anderson RA (February 1995). "The sequence of phosphatidylinositol-4-phosphate 5-kinase defines a novel family of lipid kinases". The Journal of Biological Chemistry. 270 (7): 2881–4. doi:10.1074/jbc.270.7.2881. PMID 7852364.
  6. ^ Rameh LE, Tolias KF, Duckworth BC, Cantley LC (November 1997). "A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate". Nature. 390 (6656): 192–6. Bibcode:1997Natur.390..192R. doi:10.1038/36621. PMID 9367159. S2CID 4403301.
  7. ^ a b "Entrez Gene: PIP5K2A phosphatidylinositol-4-phosphate 5-kinase, type II, alpha".
  8. ^ Xu H, Yang W, Perez-Andreu V, Devidas M, Fan Y, Cheng C, et al. (May 2013). "Novel susceptibility variants at 10p12.31-12.2 for childhood acute lymphoblastic leukemia in ethnically diverse populations". Journal of the National Cancer Institute. 105 (10): 733–42. doi:10.1093/jnci/djt042. PMC 3691938. PMID 23512250.
  9. ^ Liao F, Yin D, Zhang Y, Hou Q, Zheng Z, Yang L, Shu Y, Xu H, Li Y (May 2016). "Association Between PIP4K2A Polymorphisms and Acute Lymphoblastic Leukemia Susceptibility". Medicine. 95 (18): e3542. doi:10.1097/MD.0000000000003542. PMC 4863780. PMID 27149463.
  10. ^ 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.
  11. ^ 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.
  12. ^ "Donated Chemical Probes". 12 June 2018. Retrieved July 31, 2023.

Further reading

External links

  • 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.