Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOJMB1V)

• DOT Name: Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta (PDE6B)
• Synonyms: GMP-PDE beta; EC 3.1.4.35
• Gene Name: PDE6B
• Related Disease:
  Retinitis pigmentosa 40
  Advanced cancer
  Bardet biedl syndrome
  Cone-rod synaptic disorder, congenital nonprogressive
  Congenital stationary night blindness 1A
  Congenital stationary night blindness 1B
  Congenital stationary night blindness 2A
  Congenital stationary night blindness autosomal dominant 2
  Inherited retinal dystrophy
  Night blindness
  Stargardt disease
  Tuberculosis
  Leber congenital amaurosis
  Leber congenital amaurosis 1
  Retinal degeneration
  Congenital stationary night blindness
  Retinitis pigmentosa
  Disorder of orbital region
  Pulmonary tuberculosis
• UniProt ID: PDE6B_HUMAN
• EC Number: 3.1.4.35
• Pfam ID: PF01590 ; PF00233
• Sequence:
  MSLSEEQARSFLDQNPDFARQYFGKKLSPENVAAACEDGCPPDCDSLRDLCQVEESTALL
  ELVQDMQESINMERVVFKVLRRLCTLLQADRCSLFMYRQRNGVAELATRLFSVQPDSVLE
  DCLVPPDSEIVFPLDIGVVGHVAQTKKMVNVEDVAECPHFSSFADELTDYKTKNMLATPI
  MNGKDVVAVIMAVNKLNGPFFTSEDEDVFLKYLNFATLYLKIYHLSYLHNCETRRGQVLL
  WSANKVFEELTDIERQFHKAFYTVRAYLNCERYSVGLLDMTKEKEFFDVWSVLMGESQPY
  SGPRTPDGREIVFYKVIDYVLHGKEEIKVIPTPSADHWALASGLPSYVAESGFICNIMNA
  SADEMFKFQEGALDDSGWLIKNVLSMPIVNKKEEIVGVATFYNRKDGKPFDEQDEVLMES
  LTQFLGWSVMNTDTYDKMNKLENRKDIAQDMVLYHVKCDRDEIQLILPTRARLGKEPADC
  DEDELGEILKEELPGPTTFDIYEFHFSDLECTELDLVKCGIQMYYELGVVRKFQIPQEVL
  VRFLFSISKGYRRITYHNWRHGFNVAQTMFTLLMTGKLKSYYTDLEAFAMVTAGLCHDID
  HRGTNNLYQMKSQNPLAKLHGSSILERHHLEFGKFLLSEETLNIYQNLNRRQHEHVIHLM
  DIAIIATDLALYFKKRAMFQKIVDESKNYQDKKSWVEYLSLETTRKEIVMAMMMTACDLS
  AITKPWEVQSKVALLVAAEFWEQGDLERTVLDQQPIPMMDRNKAAELPKLQVGFIDFVCT
  FVYKEFSRFHEEILPMFDRLQNNRKEWKALADEYEAKVKALEEKEEEERVAAKKVGTEIC
  NGGPAPKSSTCCIL
• Function: Rod-specific cGMP phosphodiesterase that catalyzes the hydrolysis of 3',5'-cyclic GMP. Necessary for the formation of a functional phosphodiesterase holoenzyme. Involved in retinal circadian rhythm photoentrainment via modulation of UVA and orange light-induced phase-shift of the retina clock. May participate in processes of transmission and amplification of the visual signal.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
  Phototransduction (hsa04744)
• Reactome Pathway:
  Inactivation, recovery and regulation of the phototransduction cascade (R-HSA-2514859)
  Ca2+ pathway (R-HSA-4086398)
  Activation of the phototransduction cascade (R-HSA-2485179)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Retinitis pigmentosa 40	DISR25W6	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Bardet biedl syndrome	DISTBNZW	Strong	Genetic Variation	[3]
Cone-rod synaptic disorder, congenital nonprogressive	DIS9ZCRA	Strong	Biomarker	[4]
Congenital stationary night blindness 1A	DISCQ9B9	Strong	Biomarker	[4]
Congenital stationary night blindness 1B	DISZ8V5R	Strong	Biomarker	[4]
Congenital stationary night blindness 2A	DISA57KI	Strong	Biomarker	[4]
Congenital stationary night blindness autosomal dominant 2	DISQJU07	Strong	Autosomal dominant	[4]
Inherited retinal dystrophy	DISGGL77	Strong	Genetic Variation	[5]
Night blindness	DIS335K9	Strong	Genetic Variation	[6]
Stargardt disease	DISPXOTO	Strong	Biomarker	[7]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[8]
Leber congenital amaurosis	DISMGH8F	moderate	Genetic Variation	[9]
Leber congenital amaurosis 1	DISY2B33	moderate	Genetic Variation	[9]
Retinal degeneration	DISM1JHQ	moderate	Biomarker	[10]
Congenital stationary night blindness	DISX0CWK	Supportive	Autosomal dominant	[4]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[11]
Disorder of orbital region	DISH0ECJ	Limited	Biomarker	[12]
Pulmonary tuberculosis	DIS6FLUM	Limited	Biomarker	[8]

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 Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta (PDE6B).	[13]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta (PDE6B).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta (PDE6B).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta (PDE6B).	[15]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] T-cell Receptors Engineered De Novo for Peptide Specificity Can Mediate Optimal T-cell Activity without Self Cross-Reactivity.Cancer Immunol Res. 2019 Dec;7(12):2025-2035. doi: 10.1158/2326-6066.CIR-19-0035. Epub 2019 Sep 23.
• [3] Multiple genetic mutations implicate spectrum of phenotypes in Bardet-Biedl syndrome.Gene. 2020 Jan 30;725:144164. doi: 10.1016/j.gene.2019.144164. Epub 2019 Oct 19.
• [4] Heterozygous missense mutation in the rod cGMP phosphodiesterase beta-subunit gene in autosomal dominant stationary night blindness. Nat Genet. 1994 May;7(1):64-8. doi: 10.1038/ng0594-64.
• [5] Next-generation sequencing targeted disease panel in rod-cone retinal dystrophies in Mori and Polynesian reveals novel changes and a common founder mutation.Clin Exp Ophthalmol. 2017 Dec;45(9):901-910. doi: 10.1111/ceo.12983. Epub 2017 Jun 13.
• [6] Longitudinal Clinical Follow-up and Genetic Spectrum of Patients With Rod-Cone Dystrophy Associated With Mutations in PDE6A and PDE6B.JAMA Ophthalmol. 2019 Jun 1;137(6):669-679. doi: 10.1001/jamaophthalmol.2018.6367.
• [7] Assessment of tropism and effectiveness of new primate-derived hybrid recombinant AAV serotypes in the mouse and primate retina.PLoS One. 2013 Apr 9;8(4):e60361. doi: 10.1371/journal.pone.0060361. Print 2013.
• [8] Identification of Rv0222 from RD4 as a novel serodiagnostic target for tuberculosis.Tuberculosis (Edinb). 2008 Jul;88(4):335-43. doi: 10.1016/j.tube.2007.12.001. Epub 2008 Feb 19.
• [9] Linkage studies and mutation analysis of the PDEB gene in 23 families with Leber congenital amaurosis.Hum Mutat. 1992;1(6):478-85. doi: 10.1002/humu.1380010605.
• [10] Degeneration modulates retinal response to transient exogenous oxidative injury.PLoS One. 2014 Feb 21;9(2):e87751. doi: 10.1371/journal.pone.0087751. eCollection 2014.
• [11] Nonsyndromic Retinitis Pigmentosa Overview. 2000 Aug 4 [updated 2023 Apr 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [12] Generalized progressive retinal atrophy of Sloughi dogs is due to an 8-bp insertion in exon 21 of the PDE6B gene.Cytogenet Cell Genet. 2000;90(3-4):261-7. doi: 10.1159/000056785.
• [13] 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.
• [14] 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.
• [15] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [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.