Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBW6SGD)

• DOT Name: Alpha-protein kinase 1 (ALPK1)
• Synonyms: EC 2.7.11.1; Chromosome 4 kinase; Lymphocyte alpha-protein kinase
• Gene Name: ALPK1
• Related Disease:
  Neoplasm of esophagus
  Nephropathy
  Non-insulin dependent diabetes
  Advanced cancer
  Atrial fibrillation
  Breast cancer
  Breast carcinoma
  Colitis
  Colorectal carcinoma
  Depression
  Diabetic kidney disease
  Fibrosarcoma
  Gout
  Inherited retinal dystrophy
  Lung cancer
  Lung carcinoma
  Migraine
  Neoplasm
  Obesity
  Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome
  Rheumatoid arthritis
  Triple negative breast cancer
  Bacterial infection
  Chronic kidney disease
  Squamous cell carcinoma
  Type-1/2 diabetes
• UniProt ID: ALPK1_HUMAN
• PDB ID: 5Z2C
• EC Number: 2.7.11.1
• Pfam ID: PF02816
• Sequence:
  MNNQKVVAVLLQECKQVLDQLLLEAPDVSEEDKSEDQRCRALLPSELRTLIQEAKEMKWP
  FVPEKWQYKQAVGPEDKTNLKDVIGAGLQQLLASLRASILARDCAAAAAIVFLVDRFLYG
  LDVSGKLLQVAKGLHKLQPATPIAPQVVIRQARISVNSGKLLKAEYILSSLISNNGATGT
  WLYRNESDKVLVQSVCIQIRGQILQKLGMWYEAAELIWASIVGYLALPQPDKKGLSTSLG
  ILADIFVSMSKNDYEKFKNNPQINLSLLKEFDHHLLSAAEACKLAAAFSAYTPLFVLTAV
  NIRGTCLLSYSSSNDCPPELKNLHLCEAKEAFEIGLLTKRDDEPVTGKQELHSFVKAAFG
  LTTVHRRLHGETGTVHAASQLCKEAMGKLYNFSTSSRSQDREALSQEVMSVIAQVKEHLQ
  VQSFSNVDDRSYVPESFECRLDKLILHGQGDFQKILDTYSQHHTSVCEVFESDCGNNKNE
  QKDAKTGVCITALKTEIKNIDTVSTTQEKPHCQRDTGISSSLMGKNVQRELRRGGRRNWT
  HSDAFRVSLDQDVETETEPSDYSNGEGAVFNKSLSGSQTSSAWSNLSGFSSSASWEEVNY
  HVDDRSARKEPGKEHLVDTQCSTALSEELENDREGRAMHSLHSQLHDLSLQEPNNDNLEP
  SQNQPQQQMPLTPFSPHNTPGIFLAPGAGLLEGAPEGIQEVRNMGPRNTSAHSRPSYRSA
  SWSSDSGRPKNMGTHPSVQKEEAFEIIVEFPETNCDVKDRQGKEQGEEISERGAGPTFKA
  SPSWVDPEGETAESTEDAPLDFHRVLHNSLGNISMLPCSSFTPNWPVQNPDSRKSGGPVA
  EQGIDPDASTVDEEGQLLDSMDVPCTNGHGSHRLCILRQPPGQRAETPNSSVSGNILFPV
  LSEDCTTTEEGNQPGNMLNCSQNSSSSSVWWLKSPAFSSGSSEGDSPWSYLNSSGSSWVS
  LPGKMRKEILEARTLQPDDFEKLLAGVRHDWLFQRLENTGVFKPSQLHRAHSALLLKYSK
  KSELWTAQETIVYLGDYLTVKKKGRQRNAFWVHHLHQEEILGRYVGKDYKEQKGLWHHFT
  DVERQMTAQHYVTEFNKRLYEQNIPTQIFYIPSTILLILEDKTIKGCISVEPYILGEFVK
  LSNNTKVVKTEYKATEYGLAYGHFSYEFSNHRDVVVDLQGWVTGNGKGLIYLTDPQIHSV
  DQKVFTTNFGKRGIFYFFNNQHVECNEICHRLSLTRPSMEKPCT
• Function: Serine/threonine-protein kinase that detects bacterial pathogen-associated molecular pattern metabolites (PAMPs) and initiates an innate immune response, a critical step for pathogen elimination and engagement of adaptive immunity. Specifically recognizes and binds ADP-D-glycero-beta-D-manno-heptose (ADP-Heptose), a potent PAMP present in all Gram-negative and some Gram-positive bacteria. ADP-Heptose-binding stimulates its kinase activity to phosphorylate and activate TIFA, triggering pro-inflammatory NF-kappa-B signaling. May be involved in monosodium urate monohydrate (MSU)-induced inflammation by mediating phosphorylation of unconventional myosin MYO9A. May also play a role in apical protein transport by mediating phosphorylation of unconventional myosin MYO1A. May play a role in ciliogenesis.
• Tissue Specificity: Highly expressed in liver. Expressed in the optic nerve and retinal pigmented epithelium. Lower expression is observed in the macula and extramacular retina .
• Reactome Pathway:
  Alpha-protein kinase 1 signaling pathway (R-HSA-9645460)
  TAK1-dependent IKK and NF-kappa-B activation (R-HSA-445989)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm of esophagus	DISOLKAQ	Definitive	Biomarker	[1]
Nephropathy	DISXWP4P	Definitive	Biomarker	[2]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Colitis	DISAF7DD	Strong	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Depression	DIS3XJ69	Strong	Altered Expression	[7]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[8]
Fibrosarcoma	DISWX7MU	Strong	Biomarker	[9]
Gout	DISHC0U7	Strong	Biomarker	[8]
Inherited retinal dystrophy	DISGGL77	Strong	Genetic Variation	[10]
Lung cancer	DISCM4YA	Strong	Altered Expression	[3]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[3]
Migraine	DISQ8RM8	Strong	Genetic Variation	[10]
Neoplasm	DISZKGEW	Strong	Altered Expression	[11]
Obesity	DIS47Y1K	Strong	Genetic Variation	[12]
Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome	DISZFNVJ	Strong	Autosomal dominant	[10]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[13]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[5]
Bacterial infection	DIS5QJ9S	moderate	Biomarker	[14]
Chronic kidney disease	DISW82R7	Limited	Biomarker	[2]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[11]
Type-1/2 diabetes	DISIUHAP	Limited	Altered Expression	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Epirubicin	DMPDW6T	Approved	Alpha-protein kinase 1 (ALPK1) increases the Leukopenia ADR of Epirubicin.	[29]
Streptozocin	DMOF7AT	Approved	Alpha-protein kinase 1 (ALPK1) increases the response to substance of Streptozocin.	[8]

13 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Alpha-protein kinase 1 (ALPK1).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Alpha-protein kinase 1 (ALPK1).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Alpha-protein kinase 1 (ALPK1).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Alpha-protein kinase 1 (ALPK1).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Alpha-protein kinase 1 (ALPK1).	[19]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Alpha-protein kinase 1 (ALPK1).	[20]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Alpha-protein kinase 1 (ALPK1).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Alpha-protein kinase 1 (ALPK1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Alpha-protein kinase 1 (ALPK1).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Alpha-protein kinase 1 (ALPK1).	[25]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Alpha-protein kinase 1 (ALPK1).	[26]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Alpha-protein kinase 1 (ALPK1).	[27]
Uric acid	DMA1MKT	Investigative	Uric acid increases the expression of Alpha-protein kinase 1 (ALPK1).	[8]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Alpha-protein kinase 1 (ALPK1).	[23]

References

• [1] Cisplatin induces fas expression in esophageal cancer cell lines and enhanced cytotoxicity in combination with LAK cells.Oncology. 2000 Nov;59(4):336-43. doi: 10.1159/000012192.
• [2] ALPK1 regulates streptozotocin-induced nephropathy through CCL2 and CCL5 expressions.J Cell Mol Med. 2019 Nov;23(11):7699-7708. doi: 10.1111/jcmm.14643. Epub 2019 Sep 26.
• [3] Down-regulated and Commonly mutated ALPK1 in Lung and Colorectal Cancers.Sci Rep. 2016 Jun 10;6:27350. doi: 10.1038/srep27350.
• [4] Biobank-driven genomic discovery yields new insight into atrial fibrillation biology.Nat Genet. 2018 Sep;50(9):1234-1239. doi: 10.1038/s41588-018-0171-3. Epub 2018 Jul 30.
• [5] ERN1 and ALPK1 inhibit differentiation of bi-potential tumor-initiating cells in human breast cancer.Oncotarget. 2016 Dec 13;7(50):83278-83293. doi: 10.18632/oncotarget.13086.
• [6] Alpha kinase 1 controls intestinal inflammation by suppressing the IL-12/Th1 axis.Nat Commun. 2018 Sep 18;9(1):3797. doi: 10.1038/s41467-018-06085-5.
• [7] Induction of metastatic cancer stem cells from the NK/LAK-resistant floating, but not adherent, subset of the UP-LN1 carcinoma cell line by IFN-.Lab Invest. 2011 Oct;91(10):1502-13. doi: 10.1038/labinvest.2011.91. Epub 2011 Jun 20.
• [8] Enhanced alpha-kinase 1 accelerates multiple early nephropathies in streptozotocin-induced hyperglycemic mice. Biochim Biophys Acta. 2016 Nov;1862(11):2034-2042. doi: 10.1016/j.bbadis.2016.08.010. Epub 2016 Aug 16.
• [9] Soluble tumor necrosis factor receptor type I enhances tumor development and persistence in vivo.Cell Immunol. 2000 Mar 15;200(2):81-7. doi: 10.1006/cimm.2000.1622.
• [10] ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder. Genet Med. 2019 Sep;21(9):2103-2115. doi: 10.1038/s41436-019-0476-3. Epub 2019 Apr 10.
• [11] ALPK1 Expression Is Associated with Lymph Node Metastasis and Tumor Growth in Oral Squamous Cell Carcinoma Patients.Am J Pathol. 2019 Jan;189(1):190-199. doi: 10.1016/j.ajpath.2018.09.003. Epub 2018 Oct 11.
• [12] A genome-wide association meta-analysis identifies new childhood obesity loci.Nat Genet. 2012 May;44(5):526-31. doi: 10.1038/ng.2247.
• [13] Studying the effects of haplotype partitioning methods on the RA-associated genomic results from the North American Rheumatoid Arthritis Consortium (NARAC) dataset.J Adv Res. 2019 Jan 18;18:113-126. doi: 10.1016/j.jare.2019.01.006. eCollection 2019 Jul.
• [14] Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose.Nature. 2018 Sep;561(7721):122-126. doi: 10.1038/s41586-018-0433-3. Epub 2018 Aug 15.
• [15] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [16] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [17] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [18] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [19] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [20] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [21] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [22] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [23] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [24] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [25] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [26] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [27] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [28] Enhanced alpha-kinase 1 accelerates multiple early nephropathies in streptozotocin-induced hyperglycemic mice. Biochim Biophys Acta. 2016 Nov;1862(11):2034-2042. doi: 10.1016/j.bbadis.2016.08.010. Epub 2016 Aug 16.
• [29] Genome-wide association study of epirubicin-induced leukopenia in Japanese patients. Pharmacogenet Genomics. 2011 Sep;21(9):552-8. doi: 10.1097/FPC.0b013e328348e48f.
• [30] Enhanced alpha-kinase 1 accelerates multiple early nephropathies in streptozotocin-induced hyperglycemic mice. Biochim Biophys Acta. 2016 Nov;1862(11):2034-2042. doi: 10.1016/j.bbadis.2016.08.010. Epub 2016 Aug 16.