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phosphoinositide kinase, FYVE-type zinc finger containing

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2857

Nomenclature: phosphoinositide kinase, FYVE-type zinc finger containing

Family: 1-phosphatidylinositol-3-phosphate 5-kinase family

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 2098 2q34 PIKFYVE phosphoinositide kinase, FYVE-type zinc finger containing 13
Mouse - 2097 1 C2 Pikfyve phosphoinositide kinase, FYVE type zinc finger containing
Rat - - 9q32 Pikfyve phosphoinositide kinase, FYVE-type zinc finger containing
Previous and Unofficial Names Click here for help
FAB1 | phosphatidylinositol-3-phosphate/phosphatidylinositol 5-kinase, type III | PIP5K3 | zinc finger, FYVE domain containing 29 | phosphoinositide kinase, FYVE finger containing | phosphoinositide kinase | phosphoinositide kinase, FYVE type zinc finger containing
Database Links Click here for help
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CATH/Gene3D
ChEMBL Target
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RefSeq Protein
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Enzyme Reaction Click here for help
EC Number: 2.7.1.150 ATP + 1-phosphatidyl-1D-myo-inositol 3-phosphate = ADP + 1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
apilimod Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 7.2 pKd 3
pKd 7.2 (Kd 6.5x10-8 M) [3]
Description: Binding constant for Cy5-apilimod to PIKfyve kinase domain.
apilimod Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 7.8 pIC50 3
pIC50 7.8 (IC50 1.4x10-8 M) [3]
Description: Effect of apilimod on hPIKfyve kinase activity in vitro measuringPI(3)P conversion to PI(3,5)P2.
Immunopharmacology Comments
PIKfyve is a class III PI kinase. Evidence is revealing a crucial role for PIKfyve in Toll-like receptor (TLR) signaling via production of the cytokines IL-12 and IL-23 [3]. Pharmacological (using apilimod) or genetic inactivation of PIKfyve suppresses expression of the p40 (IL-12B) subunit shared by IL-12 and IL-23, and this has a regulatory role on TLR signaling. PIKfyve has also been implicated as a key component of antigen presentation by dendritic cells [1]. With regards to the investigation of apilimod in SARS-CoV-2 infection, inhibition of antigen presentation, the immune response to new antigens, and T-cell activation, may not be ideal in this setting. Would this leave patients susceptible to other infections during apilimod treatment? Results from the apilomod clinical trials will be interesting.
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Corneal dystrophy, Fleck
Description: A rare, autosomal dominant disease which causes the formation of numerous tiny, dot-like white flecks scattered in all layers of the corneal stroma. A few patients present with photophobia, but the majority are asymptomatic.
Synonyms: CFD
corneal dystrophy, Francois-Neetens speckled ro flecked
OMIM: 121850
Role: 
References:  7-8,10
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Frameshift: Deletion Human 4166_4169delAAGT or 4167_4170delAGTA This mutation deletes 4 nucleotides in exon 24 of the gene, leading to a truncated protein product. 7
Missense Human K1103R 3466A>G 8
General Comments
Pharmacological inhibition of PIKfyve by apilimod (STA-5326) has potent cytotoxic activity against B-cell non-Hodgkin lymphoma cells [4]. This effect is selective for the lymphoma cells compared to normal cells.

SARS-CoV-2: PIKfyve has been reported as being required for Ebola virus (EBOV) infection of host cells [11], and indeed apilimod has anti-EBOV activity in vitro. More broad-spectrum antiviral activity against Lassa virus (LASV), Marburg virus (MARV) [9] and SARS-CoV-2 [5-6,12] is supported in the literature. Activity of PIKfyve is markedly modulated by SARS-CoV-2 infection in vitro, and indicates potential hijacking of phosphatidylinositol enzyme activities by the coronavirus [2]. Pharmacological inhibition of this kinase with apilimod has anti-SARS-CoV-2 activity in two model cells lines, A549-ACE2 cells (IC50 7 nM) and Vero E6 cells (IC50 80 nM), and human iPSC-derived pneumocyte-like cells [12].

References

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1. Baranov MV, Bianchi F, Schirmacher A, van Aart MAC, Maassen S, Muntjewerff EM, Dingjan I, Ter Beest M, Verdoes M, Keyser SGL et al.. (2019) The Phosphoinositide Kinase PIKfyve Promotes Cathepsin-S-Mediated Major Histocompatibility Complex Class II Antigen Presentation. iScience, 11: 160-177. [PMID:30612035]

2. Bouhaddou M, Memon D, Meyer B, White KM, Rezelj VV, Marrero MC, Polacco BJ, Melnyk JE, Ulferts S, Kaake RM. (2020) The Global Phosphorylation Landscape of SARS-CoV-2 Infection. Cell, Article Online Now. DOI: 10.1016/j.cell.2020.06.034

3. Cai X, Xu Y, Cheung AK, Tomlinson RC, Alcázar-Román A, Murphy L, Billich A, Zhang B, Feng Y, Klumpp M et al.. (2013) PIKfyve, a class III PI kinase, is the target of the small molecular IL-12/IL-23 inhibitor apilimod and a player in Toll-like receptor signaling. Chem Biol, 20 (7): 912-21. [PMID:23890009]

4. Gayle S, Landrette S, Beeharry N, Conrad C, Hernandez M, Beckett P, Ferguson SM, Mandelkern T, Zheng M, Xu T et al.. (2017) Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma. Blood, 129 (13): 1768-1778. [PMID:28104689]

5. Ianevski A, Yao R, Fenstad MH, Biza S, Zusinaite E, Reisberg T, Lysvand H, Løseth K, Landsem VM, Malmring JF et al.. (2020) Potential Antiviral Options against SARS-CoV-2 Infection. Viruses, 12 (6). [PMID:32545799]

6. Kang YL, Chou YY, Rothlauf PW, Liu Z, Soh TK, Cureton D, Case JB, Chen RE, Diamond MS, Whelan SPJ et al.. (2020) Inhibition of PIKfyve kinase prevents infection by Zaire ebolavirus and SARS-CoV-2. Proc Natl Acad Sci U S A, 117 (34): 20803-20813. [PMID:32764148]

7. Kawasaki S, Yamasaki K, Nakagawa H, Shinomiya K, Nakatsukasa M, Nakai Y, Kinoshita S. (2012) A novel mutation (p.Glu1389AspfsX16) of the phosphoinositide kinase, FYVE finger containing gene found in a Japanese patient with fleck corneal dystrophy. Mol Vis, 18: 2954-60. [PMID:23288988]

8. Li S, Tiab L, Jiao X, Munier FL, Zografos L, Frueh BE, Sergeev Y, Smith J, Rubin B, Meallet MA et al.. (2005) Mutations in PIP5K3 are associated with François-Neetens mouchetée fleck corneal dystrophy. Am J Hum Genet, 77 (1): 54-63. [PMID:15902656]

9. Nelson EA, Dyall J, Hoenen T, Barnes AB, Zhou H, Liang JY, Michelotti J, Dewey WH, DeWald LE, Bennett RS et al.. (2017) The phosphatidylinositol-3-phosphate 5-kinase inhibitor apilimod blocks filoviral entry and infection. PLoS Negl Trop Dis, 11 (4): e0005540. [PMID:28403145]

10. Nicholson DH, Green WR, Cross HE, Kenyon KR, Massof D. (1977) A clinical and histopathological study of François-Neetens speckled corneal dystrophy. Am J Ophthalmol, 83 (4): 554-60. [PMID:141212]

11. Qiu S, Leung A, Bo Y, Kozak RA, Anand SP, Warkentin C, Salambanga FDR, Cui J, Kobinger G, Kobasa D et al.. (2018) Ebola virus requires phosphatidylinositol (3,5) bisphosphate production for efficient viral entry. Virology, 513: 17-28. [PMID:29031163]

12. Riva L, Yuan S, Yin X, Martin-Sancho L, Matsunaga N, Pache L, Burgstaller-Muehlbacher S, De Jesus PD, Teriete P, Hull MV et al.. (2020) Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Nature, [Epub ahead of print]. DOI: 10.1038/s41586-020-2577-1

13. Shisheva A, Sbrissa D, Ikonomov O. (1999) Cloning, characterization, and expression of a novel Zn2+-binding FYVE finger-containing phosphoinositide kinase in insulin-sensitive cells. Mol Cell Biol, 19 (1): 623-34. [PMID:9858586]

How to cite this page

1-phosphatidylinositol-3-phosphate 5-kinase family: phosphoinositide kinase, FYVE-type zinc finger containing. Last modified on 13/08/2020. Accessed on 25/09/2021. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2857.