Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2CZVRT)

• DOT Name: Pantothenate kinase 1 (PANK1)
• Synonyms: hPanK; hPanK1; EC 2.7.1.33; Pantothenic acid kinase 1
• Gene Name: PANK1
• Related Disease:
  Hallermann-Streiff syndrome
  Advanced cancer
  Cerebellar ataxia
  Dystonia
  Hereditary spastic paraplegia 11
  Neurodegeneration with brain iron accumulation
  Neurodegeneration with brain iron accumulation 2A
  Neurodegeneration with brain iron accumulation 5
  Neuroferritinopathy
  Pantothenate kinase-associated neurodegeneration
  Staphylococcus infection
  Malignant exocrine pancreas neoplasm
  Parkinsonian disorder
  Spondyloepiphyseal dysplasia with congenital joint dislocations
• UniProt ID: PANK1_HUMAN
• PDB ID: 2I7N; 3SMP
• EC Number: 2.7.1.33
• Pfam ID: PF03630
• Sequence:
  MLKLVGGGGGQDWACSVAGTSLGGEEAAFEVARPGDQGKAGGGSPGWGCAGIPDSAPGAG
  VLQAGAVGPARGGQGAEEVGESAGGGEERRVRHPQAPALRLLNRKPQGGSGEIKTPENDL
  QRGRLSRGPRTAPPAPGMGDRSGQQERSVPHSPGAPVGTSAAAVNGLLHNGFHPPPVQPP
  HVCSRGPVGGSDAAPQRLPLLPELQPQPLLPQHDSPAKKCRLRRRMDSGRKNRPPFPWFG
  MDIGGTLVKLVYFEPKDITAEEEQEEVENLKSIRKYLTSNTAYGKTGIRDVHLELKNLTM
  CGRKGNLHFIRFPSCAMHRFIQMGSEKNFSSLHTTLCATGGGAFKFEEDFRMIADLQLHK
  LDELDCLIQGLLYVDSVGFNGKPECYYFENPTNPELCQKKPYCLDNPYPMLLVNMGSGVS
  ILAVYSKDNYKRVTGTSLGGGTFLGLCCLLTGCETFEEALEMAAKGDSTNVDKLVKDIYG
  GDYERFGLQGSAVASSFGNMMSKEKRDSISKEDLARATLVTITNNIGSIARMCALNENID
  RVVFVGNFLRINMVSMKLLAYAMDFWSKGQLKALFLEHEGYFGAVGALLELFKMTDDK
• Function: [Isoform 1]: Catalyzes the phosphorylation of pantothenate to generate 4'-phosphopantothenate in the first and rate-determining step of coenzyme A (CoA) synthesis.
• Tissue Specificity: .Expressed at high levels in brain, heart, kidney, liver, skeletal muscle and testis.; [Isoform 2]: Detected at much lower levels in kidney, liver, brain and testis and not detected in heart or skeletal muscle.
• KEGG Pathway:
  Pantothe.te and CoA biosynthesis (hsa00770)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Coenzyme A biosynthesis (R-HSA-196783)
• BioCyc Pathway: MetaCyc:HS07852-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hallermann-Streiff syndrome	DISNT5DL	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[3]
Dystonia	DISJLFGW	Strong	Genetic Variation	[4]
Hereditary spastic paraplegia 11	DIS8K8V4	Strong	Genetic Variation	[4]
Neurodegeneration with brain iron accumulation	DISRK4DZ	Strong	Genetic Variation	[5]
Neurodegeneration with brain iron accumulation 2A	DIS9XEBF	Strong	Genetic Variation	[5]
Neurodegeneration with brain iron accumulation 5	DISW9SFJ	Strong	Genetic Variation	[4]
Neuroferritinopathy	DIS0E4F3	Strong	Biomarker	[4]
Pantothenate kinase-associated neurodegeneration	DIS50V55	Strong	Genetic Variation	[6]
Staphylococcus infection	DISY8WGS	Strong	Biomarker	[7]
Malignant exocrine pancreas neoplasm	DISIA6JF	moderate	Genetic Variation	[8]
Parkinsonian disorder	DISHGY45	Limited	Biomarker	[4]
Spondyloepiphyseal dysplasia with congenital joint dislocations	DISR9PTZ	Limited	Genetic Variation	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Pantothenate kinase 1 (PANK1).	[10]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Pantothenate kinase 1 (PANK1).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Pantothenate kinase 1 (PANK1).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Pantothenate kinase 1 (PANK1).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Pantothenate kinase 1 (PANK1).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Pantothenate kinase 1 (PANK1).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Pantothenate kinase 1 (PANK1).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Pantothenate kinase 1 (PANK1).	[15]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Pantothenate kinase 1 (PANK1).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pantothenate kinase 1 (PANK1).	[16]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Pantothenate kinase 1 (PANK1).	[18]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Pantothenate kinase 1 (PANK1).	[19]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Pantothenate kinase 1 (PANK1).	[20]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Pantothenate kinase 1 (PANK1).	[21]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Pantothenate kinase 1 (PANK1).	[22]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Pantothenate kinase 1 (PANK1).	[15]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Pantothenate kinase 1 (PANK1).	[23]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of Pantothenate kinase 1 (PANK1).	[15]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of Pantothenate kinase 1 (PANK1).	[15]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil decreases the expression of Pantothenate kinase 1 (PANK1).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Pantothenate kinase 1 (PANK1).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Pantothenate kinase 1 (PANK1).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Pantothenate kinase 1 (PANK1).	[26]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Pantothenate kinase 1 (PANK1).	[27]

References

• [1] A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat Genet. 2001 Aug;28(4):345-9. doi: 10.1038/ng572.
• [2] Ki-ras mutations as a prognostic factor in extrahepatic bile system cancer. PANK-ras I Project Investigators.J Clin Oncol. 1995 Jul;13(7):1679-86. doi: 10.1200/JCO.1995.13.7.1679.
• [3] Deep brain stimulation as a mode of treatment of early onset pantothenate kinase-associated neurodegeneration.Eur J Paediatr Neurol. 2009 Jan;13(1):61-4. doi: 10.1016/j.ejpn.2008.01.006. Epub 2008 May 6.
• [4] Rare causes of dystonia parkinsonism.Curr Neurol Neurosci Rep. 2010 Nov;10(6):431-9. doi: 10.1007/s11910-010-0136-0.
• [5] Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations.Neurobiol Aging. 2012 Apr;33(4):814-23. doi: 10.1016/j.neurobiolaging.2010.05.009. Epub 2010 Jul 21.
• [6] A therapeutic approach to pantothenate kinase associated neurodegeneration.Nat Commun. 2018 Oct 23;9(1):4399. doi: 10.1038/s41467-018-06703-2.
• [7] Inhibitors of pantothenate kinase: novel antibiotics for staphylococcal infections.Antimicrob Agents Chemother. 2003 Jun;47(6):2051-5. doi: 10.1128/AAC.47.6.2051-2055.2003.
• [8] Ki-ras mutations in exocrine pancreatic cancer: association with clinico-pathological characteristics and with tobacco and alcohol consumption. PANK-ras I Project Investigators.Int J Cancer. 1997 Mar 17;70(6):661-7. doi: 10.1002/(sici)1097-0215(19970317)70:6<661::aid-ijc6>3.0.co;2-t.
• [9] Familial pediatric rapidly progressive extrapyramidal syndrome: is it Hallervorden-Spatz disease?.Pediatr Neurol. 2003 Aug;29(2):170-2. doi: 10.1016/s0887-8994(03)00231-5.
• [10] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [11] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [12] 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.
• [13] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [16] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [17] Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood. Epigenetics. 2014 May;9(5):774-82. doi: 10.4161/epi.28153. Epub 2014 Feb 13.
• [18] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [19] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [20] Transcriptional profiling of MCF7 breast cancer cells in response to 5-Fluorouracil: relationship with cell cycle changes and apoptosis, and identification of novel targets of p53. Int J Cancer. 2006 Sep 1;119(5):1164-75.
• [21] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [22] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [23] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [26] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [27] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [28] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.