Details of Drug Off-Target (DOT)

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

• DOT Name: Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta (PDE6D)
• Synonyms: GMP-PDE delta; Protein p17
• Gene Name: PDE6D
• Related Disease:
  Carcinoma of liver and intrahepatic biliary tract
  Ciliopathy
  Hepatocellular carcinoma
  Joubert syndrome
  Joubert syndrome 22
  Liver cancer
  Neoplasm
  Polydactyly
  Orofaciodigital syndrome type 6
  Joubert syndrome 17
• UniProt ID: PDE6D_HUMAN
• PDB ID: 1KSG ; 1KSH ; 1KSJ ; 3T5G ; 3T5I ; 4JHP ; 4JV6 ; 4JV8 ; 4JVB ; 4JVF ; 5E80 ; 5E8F ; 5F2U ; 5ML2 ; 5ML3 ; 5ML4 ; 5ML6 ; 5ML8 ; 5NAL ; 5TAR ; 5TB5 ; 5X72 ; 5X73 ; 5X74 ; 5YAV ; 5YAW ; 7PAC ; 7PAD ; 7PAE ; 7Q9Q ; 7Q9R ; 7Q9S ; 7Q9U ; 7QF9 ; 7QJK
• Pfam ID: PF05351
• Sequence:
  MSAKDERAREILRGFKLNWMNLRDAETGKILWQGTEDLSVPGVEHEARVPKKILKCKAVS
  RELNFSSTEQMEKFRLEQKVYFKGQCLEEWFFEFGFVIPNSTNTWQSLIEAAPESQMMPA
  SVLTGNVIIETKFFDDDLLVSTSRVRLFYV
• Function: Promotes the release of prenylated target proteins from cellular membranes. Modulates the activity of prenylated or palmitoylated Ras family members by regulating their subcellular location. Required for normal ciliary targeting of farnesylated target proteins, such as INPP5E. Modulates the subcellular location of target proteins by acting as a GTP specific dissociation inhibitor (GDI). Increases the affinity of ARL3 for GTP by several orders of magnitude. Stabilizes ARL3-GTP by decreasing the nucleotide dissociation rate.
• Tissue Specificity: Widely expressed. Detected in various tissues including spleen, prostate gland, testis, ovary, small intestine, colon, retina, and peripheral blood.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  RAS processing (R-HSA-9648002)
  ARL13B-mediated ciliary trafficking of INPP5E (R-HSA-5624958)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Altered Expression	[1]
Ciliopathy	DIS10G4I	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[1]
Joubert syndrome	DIS7P5CO	Strong	Biomarker	[3]
Joubert syndrome 22	DIS7MV36	Strong	Autosomal recessive	[4]
Liver cancer	DISDE4BI	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Polydactyly	DIS25BMZ	moderate	Biomarker	[2]
Orofaciodigital syndrome type 6	DISQY7K4	Supportive	Autosomal recessive	[2]
Joubert syndrome 17	DIS9LHZ1	Limited	Autosomal recessive	[2]

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 Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta (PDE6D).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta (PDE6D).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta (PDE6D).	[16]

9 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 Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta (PDE6D).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta (PDE6D).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta (PDE6D).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta (PDE6D).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta (PDE6D).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta (PDE6D).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta (PDE6D).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta (PDE6D).	[14]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta (PDE6D).	[15]

References

• [1] The Delta Subunit of Rod-Specific Photoreceptor cGMP Phosphodiesterase (PDE6D) Contributes to Hepatocellular Carcinoma Progression.Cancers (Basel). 2019 Mar 21;11(3):398. doi: 10.3390/cancers11030398.
• [2] A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium. Hum Mutat. 2014 Jan;35(1):137-46. doi: 10.1002/humu.22470.
• [3] A novel PDE6D mutation in a patient with Joubert syndrome type 22 (JBTS22).Eur J Med Genet. 2019 Nov;62(11):103576. doi: 10.1016/j.ejmg.2018.11.010. Epub 2018 Nov 10.
• [4] Deletion of PrBP/delta impedes transport of GRK1 and PDE6 catalytic subunits to photoreceptor outer segments. Proc Natl Acad Sci U S A. 2007 May 22;104(21):8857-62. doi: 10.1073/pnas.0701681104. Epub 2007 May 11.
• [5] 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.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [11] 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.
• [12] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [13] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [14] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [15] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [16] 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.