Details of Drug Off-Target (DOT)

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

• DOT Name: 4'-phosphopantetheine phosphatase (PANK4)
• Synonyms: EC 3.1.3.-; Inactive pantothenic acid kinase 4; hPanK4
• Gene Name: PANK4
• Related Disease:
  Cataract
  Cataract 9 multiple types
  Early-onset posterior polar cataract
  Cataract 49
• UniProt ID: PANK4_HUMAN
• EC Number: 3.1.3.-
• Pfam ID: PF01937 ; PF03630
• Sequence:
  MAECGASGSGSSGDSLDKSITLPPDEIFRNLENAKRFAIDIGGSLTKLAYYSTVQHKVAK
  VRSFDHSGKDTEREHEPPYEISVQEEITARLHFIKFENTYIEACLDFIKDHLVNTETKVI
  QATGGGAYKFKDLIEEKLRLKVDKEDVMTCLIKGCNFVLKNIPHEAFVYQKDSDPEFRFQ
  TNHPHIFPYLLVNIGSGVSIVKVETEDRFEWVGGSSIGGGTFWGLGALLTKTKKFDELLH
  LASRGQHSNVDMLVRDVYGGAHQTLGLSGNLIASSFGKSATADQEFSKEDMAKSLLHMIS
  NDIGQLACLHARLHSLDRVYFGGFFIRGHPVTMRTITYSINFFSKGEVQALFLRHEGYLG
  AIGAFLKGAEQDNPNQYSWGENYAGSSGLMSASPELGPAQRARSGTFDLLEMDRLERPLV
  DLPLLLDPPSYVPDTVDLTDDALARKYWLTCFEEALDGVVKRAVASQPDSVDAAERAEKF
  RQKYWNKLQTLRQQPFAYGTLTVRSLLDTREHCLNEFNFPDPYSKVKQRENGVALRCFPG
  VVRSLDALGWEERQLALVKGLLAGNVFDWGAKAVSAVLESDPYFGFEEAKRKLQERPWLV
  DSYSEWLQRLKGPPHKCALIFADNSGIDIILGVFPFVRELLLRGTEVILACNSGPALNDV
  THSESLIVAERIAGMDPVVHSALQEERLLLVQTGSSSPCLDLSRLDKGLAALVRERGADL
  VVIEGMGRAVHTNYHAALRCESLKLAVIKNAWLAERLGGRLFSVIFKYEVPAE
• Function: Phosphatase which shows a preference for 4'-phosphopantetheine and its oxidatively damaged forms (sulfonate or S-sulfonate), providing strong indirect evidence that the phosphatase activity pre-empts damage in the coenzyme A (CoA) pathway. Hydrolyzing excess 4'-phosphopantetheine could constitute a directed overflow mechanism to prevent its oxidation to the S-sulfonate, sulfonate, or other forms. Hydrolyzing 4'-phosphopantetheine sulfonate or S-sulfonate would forestall their conversion to inactive forms of CoA and acyl carrier protein. May play a role in the physiological regulation of CoA intracellular levels (Probable).
• Tissue Specificity: Widely expressed with high expression in the muscle . Expressed in the retina and lens epithelium, mainly in ganglion cell layer, outer plexiform layer and retinal pigment layer (at protein level) .
• Reactome Pathway: Vitamin B5 (pantothenate) metabolism (R-HSA-199220)
• BioCyc Pathway: MetaCyc:HS08249-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cataract	DISUD7SL	Strong	Altered Expression	[1]
Cataract 9 multiple types	DIS9JQ8P	Strong	Genetic Variation	[1]
Early-onset posterior polar cataract	DISJFK9W	Supportive	Autosomal dominant	[1]
Cataract 49	DISPQWWK	Limited	Unknown	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of 4'-phosphopantetheine phosphatase (PANK4).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of 4'-phosphopantetheine phosphatase (PANK4).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of 4'-phosphopantetheine phosphatase (PANK4).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of 4'-phosphopantetheine phosphatase (PANK4).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 4'-phosphopantetheine phosphatase (PANK4).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of 4'-phosphopantetheine phosphatase (PANK4).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of 4'-phosphopantetheine phosphatase (PANK4).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 4'-phosphopantetheine phosphatase (PANK4).	[7]
Selenium	DM25CGV	Approved	Selenium increases the expression of 4'-phosphopantetheine phosphatase (PANK4).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 4'-phosphopantetheine phosphatase (PANK4).	[11]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of 4'-phosphopantetheine phosphatase (PANK4).	[12]

References

• [1] A novel mutation of PANK4 causes autosomal dominant congenital posterior cataract. Hum Mutat. 2019 Apr;40(4):380-391. doi: 10.1002/humu.23696. Epub 2019 Jan 23.
• [2] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] 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.
• [8] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [9] 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.
• [10] 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.
• [11] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [12] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.