Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT85S0J3)

• DOT Name: Guanylyl cyclase-activating protein 2 (GUCA1B)
• Synonyms: GCAP 2; Guanylate cyclase activator 1B
• Gene Name: GUCA1B
• Related Disease:
  B-cell lymphoma
  Cone dystrophy
  Cone-rod dystrophy 2
  Large cell lymphoma
  Myeloid leukaemia
  Retinitis pigmentosa 48
  Retinopathy
  Disorder of orbital region
  Leber congenital amaurosis
  Retinitis pigmentosa
  Blindness
  Cone-rod dystrophy
  Inherited retinal dystrophy
• UniProt ID: GUC1B_HUMAN
• Pfam ID: PF13499
• Sequence:
  MGQEFSWEEAEAAGEIDVAELQEWYKKFVMECPSGTLFMHEFKRFFKVTDDEEASQYVEG
  MFRAFDKNGDNTIDFLEYVAALNLVLRGTLEHKLKWTFKIYDKDGNGCIDRLELLNIVEG
  IYQLKKACRRELQTEQGQLLTPEEVVDRIFLLVDENGDGQLSLNEFVEGARRDKWVMKML
  QMDMNPSSWLAQQRRKSAMF
• Function: Stimulates two retinal guanylyl cyclases (GCs) GUCY2D and GUCY2F when free calcium ions concentration is low, and inhibits GUCY2D and GUCY2F when free calcium ions concentration is elevated. This Ca(2+)-sensitive regulation of GCs is a key event in recovery of the dark state of rod photoreceptors following light exposure. May be involved in cone photoreceptor response and recovery of response in bright light.
• Tissue Specificity: In the retina, it is expressed in cone and rod photoreceptor cells.
• KEGG Pathway: Phototransduction (hsa04744)
• Reactome Pathway: Inactivation, recovery and regulation of the phototransduction cascade (R-HSA-2514859)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[1]
Cone dystrophy	DIS7SAZZ	Strong	Genetic Variation	[2]
Cone-rod dystrophy 2	DISX2RWY	Strong	Genetic Variation	[2]
Large cell lymphoma	DISYZHCP	Strong	Biomarker	[1]
Myeloid leukaemia	DISMN944	Strong	Biomarker	[1]
Retinitis pigmentosa 48	DIS6YSS4	Strong	Autosomal dominant	[3]
Retinopathy	DISB4B0F	Strong	Genetic Variation	[2]
Disorder of orbital region	DISH0ECJ	moderate	Biomarker	[2]
Leber congenital amaurosis	DISMGH8F	moderate	Genetic Variation	[4]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[5]
Blindness	DISTIM10	Limited	Genetic Variation	[6]
Cone-rod dystrophy	DISY9RWN	Limited	Genetic Variation	[2]
Inherited retinal dystrophy	DISGGL77	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Guanylyl cyclase-activating protein 2 (GUCA1B).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Guanylyl cyclase-activating protein 2 (GUCA1B).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Guanylyl cyclase-activating protein 2 (GUCA1B).	[10]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Guanylyl cyclase-activating protein 2 (GUCA1B).	[11]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Guanylyl cyclase-activating protein 2 (GUCA1B).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Guanylyl cyclase-activating protein 2 (GUCA1B).	[13]

References

• [1] Induction of leukemia cell differentiation and apoptosis by recombinant P48, a modulin derived from Mycoplasma fermentans.Biochem Biophys Res Commun. 2000 Mar 5;269(1):284-9. doi: 10.1006/bbrc.2000.2282.
• [2] Mutation screening of the GUCA1B gene in patients with autosomal dominant cone and cone rod dystrophy.Ophthalmic Genet. 2011 Sep;32(3):151-5. doi: 10.3109/13816810.2011.559650. Epub 2011 Mar 15.
• [3] Mutations in the gene coding for guanylate cyclase-activating protein 2 (GUCA1B gene) in patients with autosomal dominant retinal dystrophies. Graefes Arch Clin Exp Ophthalmol. 2005 Mar;243(3):235-42. doi: 10.1007/s00417-004-1015-7. Epub 2004 Sep 28.
• [4] Evaluating the role of retinal membrane guanylyl cyclase 1 (RetGC1) domains in binding guanylyl cyclase-activating proteins (GCAPs).J Biol Chem. 2015 Mar 13;290(11):6913-24. doi: 10.1074/jbc.M114.629642. Epub 2015 Jan 23.
• [5] 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.
• [6] Molecular determinants of Guanylate Cyclase Activating Protein subcellular distribution in photoreceptor cells of the retina.Sci Rep. 2018 Feb 13;8(1):2903. doi: 10.1038/s41598-018-20893-1.
• [7] A novel locus for autosomal dominant cone and cone-rod dystrophies maps to the 6p gene cluster of retinal dystrophies.Invest Ophthalmol Vis Sci. 2005 Oct;46(10):3539-44. doi: 10.1167/iovs.05-0331.
• [8] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [12] 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.
• [13] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.