Details of Drug Off-Target (DOT)

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

• DOT Name: Guanylate cyclase soluble subunit alpha-1 (GUCY1A1)
• Synonyms: GCS-alpha-1; EC 4.6.1.2; Guanylate cyclase soluble subunit alpha-3; GCS-alpha-3; Soluble guanylate cyclase large subunit
• Gene Name: GUCY1A1
• Related Disease:
  Arteriosclerosis
  Atherosclerosis
  Cardiovascular disease
  Colon cancer
  Colonic neoplasm
  Diabetic kidney disease
  Moyamoya disease with early-onset achalasia
  Myocardial infarction
  OPTN-related open angle glaucoma
  Stroke
  Thrombosis
  High blood pressure
  Moyamoya disease
  Achalasia
  Coronary atherosclerosis
  Coronary heart disease
  Glioma
• UniProt ID: GCYA1_HUMAN
• PDB ID: 3UVJ; 4NI2; 6JT0; 6JT1; 6JT2; 7D9R; 7D9S; 7D9T; 7D9U; 8HBE; 8HBF; 8HBH
• EC Number: 4.6.1.2
• Pfam ID: PF00211 ; PF07701
• Sequence:
  MFCTKLKDLKITGECPFSLLAPGQVPNESSEEAAGSSESCKATVPICQDIPEKNIQESLP
  QRKTSRSRVYLHTLAESICKLIFPEFERLNVALQRTLAKHKIKESRKSLEREDFEKTIAE
  QAVAAGVPVEVIKESLGEEVFKICYEEDENILGVVGGTLKDFLNSFSTLLKQSSHCQEAG
  KRGRLEDASILCLDKEDDFLHVYYFFPKRTTSLILPGIIKAAAHVLYETEVEVSLMPPCF
  HNDCSEFVNQPYLLYSVHMKSTKPSLSPSKPQSSLVIPTSLFCKTFPFHFMFDKDMTILQ
  FGNGIRRLMNRRDFQGKPNFEEYFEILTPKINQTFSGIMTMLNMQFVVRVRRWDNSVKKS
  SRVMDLKGQMIYIVESSAILFLGSPCVDRLEDFTGRGLYLSDIPIHNALRDVVLIGEQAR
  AQDGLKKRLGKLKATLEQAHQALEEEKKKTVDLLCSIFPCEVAQQLWQGQVVQAKKFSNV
  TMLFSDIVGFTAICSQCSPLQVITMLNALYTRFDQQCGELDVYKVETIGDAYCVAGGLHK
  ESDTHAVQIALMALKMMELSDEVMSPHGEPIKMRIGLHSGSVFAGVVGVKMPRYCLFGNN
  VTLANKFESCSVPRKINVSPTTYRLLKDCPGFVFTPRSREELPPNFPSEIPGICHFLDAY
  QQGTNSKPCFQKKDVEDGNANFLGKASGID
• Tissue Specificity: Detected in brain cortex and lung (at protein level).
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
  cGMP-PKG sig.ling pathway (hsa04022)
  Vascular smooth muscle contraction (hsa04270)
  Gap junction (hsa04540)
  Platelet activation (hsa04611)
  Circadian entrainment (hsa04713)
  Long-term depression (hsa04730)
  Oxytocin sig.ling pathway (hsa04921)
  Renin secretion (hsa04924)
  Salivary secretion (hsa04970)
• Reactome Pathway:
  Smooth Muscle Contraction (R-HSA-445355)
  Nitric oxide stimulates guanylate cyclase (R-HSA-392154)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[1]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[1]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[3]
Diabetic kidney disease	DISJMWEY	Strong	Genetic Variation	[4]
Moyamoya disease with early-onset achalasia	DIS5TCD0	Strong	Autosomal recessive	[5]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[6]
OPTN-related open angle glaucoma	DISDR98A	Strong	Biomarker	[7]
Stroke	DISX6UHX	Strong	Genetic Variation	[6]
Thrombosis	DIS2TXP8	Strong	Biomarker	[8]
High blood pressure	DISY2OHH	moderate	Biomarker	[9]
Moyamoya disease	DISO62CA	moderate	Genetic Variation	[10]
Achalasia	DISK845N	Limited	Genetic Variation	[10]
Coronary atherosclerosis	DISKNDYU	Limited	Genetic Variation	[11]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[11]
Glioma	DIS5RPEH	Limited	Altered Expression	[12]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Nitric Oxide	DM1RBYG	Approved	Guanylate cyclase soluble subunit alpha-1 (GUCY1A1) increases the response to substance of Nitric Oxide.	[26]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cyclic guanosine monophosphate	DMOU93V	Investigative	Guanylate cyclase soluble subunit alpha-1 (GUCY1A1) increases the abundance of Cyclic guanosine monophosphate.	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Guanylate cyclase soluble subunit alpha-1 (GUCY1A1).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Guanylate cyclase soluble subunit alpha-1 (GUCY1A1).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Guanylate cyclase soluble subunit alpha-1 (GUCY1A1).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Guanylate cyclase soluble subunit alpha-1 (GUCY1A1).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Guanylate cyclase soluble subunit alpha-1 (GUCY1A1).	[17]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Guanylate cyclase soluble subunit alpha-1 (GUCY1A1).	[18]
Panobinostat	DM58WKG	Approved	Panobinostat affects the expression of Guanylate cyclase soluble subunit alpha-1 (GUCY1A1).	[19]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Guanylate cyclase soluble subunit alpha-1 (GUCY1A1).	[20]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Guanylate cyclase soluble subunit alpha-1 (GUCY1A1).	[21]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Guanylate cyclase soluble subunit alpha-1 (GUCY1A1).	[22]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 affects the expression of Guanylate cyclase soluble subunit alpha-1 (GUCY1A1).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Guanylate cyclase soluble subunit alpha-1 (GUCY1A1).	[24]
Taurine	DMVW7N3	Investigative	Taurine decreases the expression of Guanylate cyclase soluble subunit alpha-1 (GUCY1A1).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Guanylate cyclase soluble subunit alpha-1 (GUCY1A1).	[23]

References

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• [2] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [3] Global gene expression analysis of rat colon cancers induced by a food-borne carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.Carcinogenesis. 2004 Aug;25(8):1495-505. doi: 10.1093/carcin/bgh155. Epub 2004 Apr 1.
• [4] Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND).PLoS Genet. 2015 Aug 25;11(8):e1005352. doi: 10.1371/journal.pgen.1005352. eCollection 2015 Aug.
• [5] 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.
• [6] Genetic variation at the coronary artery disease risk locus GUCY1A3 modifies cardiovascular disease prevention effects of aspirin.Eur Heart J. 2019 Nov 1;40(41):3385-3392. doi: 10.1093/eurheartj/ehz384.
• [7] Soluble guanylate cyclase 1-deficient mice: a novel murine model for primary open angle glaucoma.PLoS One. 2013;8(3):e60156. doi: 10.1371/journal.pone.0060156. Epub 2013 Mar 20.
• [8] Dysfunctional nitric oxide signalling increases risk of myocardial infarction.Nature. 2013 Dec 19;504(7480):432-6. doi: 10.1038/nature12722. Epub 2013 Nov 10.
• [9] Hypertension reduces soluble guanylyl cyclase expression in the mouse aorta via the Notch signaling pathway.Sci Rep. 2017 May 2;7(1):1334. doi: 10.1038/s41598-017-01392-1.
• [10] Whole exome sequencing identifies MRVI1 as a susceptibility gene for moyamoya syndrome in neurofibromatosis type 1.PLoS One. 2018 Jul 12;13(7):e0200446. doi: 10.1371/journal.pone.0200446. eCollection 2018.
• [11] Association of the coronary artery disease risk gene GUCY1A3 with ischaemic events after coronary intervention.Cardiovasc Res. 2019 Aug 1;115(10):1512-1518. doi: 10.1093/cvr/cvz015.
• [12] Inhibition of angiogenesis in human glioma cell lines by antisense RNA from the soluble guanylate cyclase genes, GUCY1A3 and GUCY1B3.Oncol Rep. 2004 Jul;12(1):47-52.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] 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.
• [15] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [16] 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.
• [17] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [18] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [19] The Bromodomain Inhibitor JQ1 and the Histone Deacetylase Inhibitor Panobinostat Synergistically Reduce N-Myc Expression and Induce Anticancer Effects. Clin Cancer Res. 2016 May 15;22(10):2534-44. doi: 10.1158/1078-0432.CCR-15-1666. Epub 2016 Jan 5.
• [20] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [21] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [22] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [23] 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.
• [24] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [25] Taurine-responsive genes related to signal transduction as identified by cDNA microarray analyses of HepG2 cells. J Med Food. 2006 Spring;9(1):33-41. doi: 10.1089/jmf.2006.9.33.
• [26] 1-A680T variant in GUCY1A3 as a candidate conferring protection from pulmonary hypertension among Kyrgyz highlanders. Circ Cardiovasc Genet. 2014 Dec;7(6):920-9. doi: 10.1161/CIRCGENETICS.114.000763. Epub 2014 Nov 4.