phosphoinositide kinase, FYVE-type zinc finger containing

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
Species	TM	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Human	-	2098	2q34	PIKFYVE	phosphoinositide kinase, FYVE-type zinc finger containing	14
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
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

Previous and Unofficial Names

Database Links
Alphafold	Q9Y2I7 (Hs), Q9Z1T6 (Mm)
BRENDA	2.7.1.150
CATH/Gene3D	3.30.40.10, 3.30.800.10, 3.30.810.10, 3.50.7.10, 1.10.10.10
ChEMBL Target	CHEMBL1938222 (Hs), CHEMBL2176842 (Mm)
Ensembl Gene	ENSG00000115020 (Hs), ENSMUSG00000025949 (Mm), ENSRNOG00000015158 (Rn)
Entrez Gene	200576 (Hs), 18711 (Mm), 316457 (Rn)
Human Protein Atlas	ENSG00000115020 (Hs)
KEGG Enzyme	2.7.1.150
KEGG Gene	hsa:200576 (Hs), mmu:18711 (Mm), rno:316457 (Rn)
OMIM	121850 (Hs), 609414 (Hs)
Pharos	Q9Y2I7 (Hs)
RefSeq Nucleotide	NM_015040 (Hs), NM_011086 (Mm)
RefSeq Protein	NP_055855 (Hs), NP_035216 (Mm)
UniProtKB	Q9Y2I7 (Hs), Q9Z1T6 (Mm)
Wikipedia	PIKFYVE (Hs)

Enzyme Reaction

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

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Ligand		Sp.	Action	Value	Parameter	Reference
apilimod		Hs	Inhibition	7.2	pK_d	3
⤷	pK_d 7.2 (K_d 6.5x10^-8 M) [3] Description: Binding constant for Cy5-apilimod to PIKfyve kinase domain.
AMG28		Hs	Inhibition	8.7	pIC₅₀	4
⤷	pIC₅₀ 8.7 (IC₅₀ 2.2x10^-9 M) [4]
compound 17 [PMID: 36111834]		Hs	Inhibition	8.2 – 8.4	pIC₅₀	4
⤷	pIC₅₀ 8.4 (IC₅₀ 4.01x10^-9 M) [4] Description: Determined in a cell-based NanoBRET assay pIC₅₀ 8.2 (IC₅₀ 6.9x10^-9 M) [4] Description: Inhibition of hPIKFYVE in a proprietary ADP-Glo enzymatic assay
apilimod		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.

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

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:

The PIKFYVE protein kinase regulates the sorting and traffic of peripheral endosomes that contain lysosomally directed fluid phase cargo, by controlling the morphogenesis and function of multivesicular bodies. Mutations in the gene are associated with CFD, and appear to cause symptomatic corneal flecks composed of abnormal keratinocytes swollen with intracytoplasmic vesicles containing complex lipids and glycosaminoglycans.

References:

8-9,11

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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.	8
Missense	Human	K1103R	3466A>G		9

General Comments
Pharmacological inhibition of PIKfyve by apilimod (STA-5326) has potent cytotoxic activity against B-cell non-Hodgkin lymphoma cells [5]. 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 [12], and indeed apilimod has anti-EBOV activity in vitro. More broad-spectrum antiviral activity against Lassa virus (LASV), Marburg virus (MARV) [10] and SARS-CoV-2 [6-7,13] 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 [13].

General Comments

Pharmacological inhibition of PIKfyve by apilimod (STA-5326) has potent cytotoxic activity against B-cell non-Hodgkin lymphoma cells [5]. 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 [12], and indeed apilimod has anti-EBOV activity in vitro. More broad-spectrum antiviral activity against Lassa virus (LASV), Marburg virus (MARV) [10] and SARS-CoV-2 [6-7,13] 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 [13].

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. Drewry DH, Potjewyd FM, Bayati A, Smith JL, Dickmander RJ, Howell S, Taft-Benz S, Min SM, Hossain MA, Heise M et al.. (2022) Identification and Utilization of a Chemical Probe to Interrogate the Roles of PIKfyve in the Lifecycle of β-Coronaviruses. J Med Chem, 65 (19): 12860-12882. [PMID:36111834]

5. 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]

6. 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]

7. 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]

8. 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]

9. 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]

10. 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]

11. 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]

12. 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]

13. 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

14. 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 20/09/2022. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2857.

phosphoinositide kinase, FYVE-type zinc finger containing

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References

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