Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR6DVAA)

• DOT Name: Guanylate cyclase soluble subunit alpha-2 (GUCY1A2)
• Synonyms: GCS-alpha-2; EC 4.6.1.2
• Gene Name: GUCY1A2
• Related Disease:
  Autism
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colorectal carcinoma
  Colorectal neoplasm
• UniProt ID: GCYA2_HUMAN
• EC Number: 4.6.1.2
• Pfam ID: PF00211 ; PF07700 ; PF07701
• Sequence:
  MSRRKISSESFSSLGSDYLETSPEEEGECPLSRLCWNGSRSPPGPLEPSPAAAAAAAAPA
  PTPAASAAAAAATAGARRVQRRRRVNLDSLGESISRLTAPSPQTIQQTLKRTLQYYEHQV
  IGYRDAEKNFHNISNRCSYADHSNKEEIEDVSGILQCTANILGLKFEEIQKRFGEEFFNI
  CFHENERVLRAVGGTLQDFFNGFDALLEHIRTSFGKQATLESPSFLCKELPEGTLMLHYF
  HPHHIVGFAMLGMIKAAGKKIYRLDVEVEQVANEKLCSDVSNPGNCSCLTFLIKECENTN
  IMKNLPQGTSQVPADLRISINTFCRAFPFHLMFDPSMSVLQLGEGLRKQLRCDTHKVLKF
  EDCFEIVSPKVNATFERVLLRLSTPFVIRTKPEASGSENKDKVMEVKGQMIHVPESNSIL
  FLGSPCVDKLDELMGRGLHLSDIPIHDATRDVILVGEQAKAQDGLKKRMDKLKATLERTH
  QALEEEKKKTVDLLYSIFPGDVAQQLWQGQQVQARKFDDVTMLFSDIVGFTAICAQCTPM
  QVISMLNELYTRFDHQCGFLDIYKVETIGDAYCVAAGLHRKSLCHAKPIALMALKMMELS
  EEVLTPDGRPIQMRIGIHSGSVLAGVVGVRMPRYCLFGNNVTLASKFESGSHPRRINVSP
  TTYQLLKREESFTFIPRSREELPDNFPKEIPGICYFLEVRTGPKPPKPSLSSSRIKKVSY
  NIGTMFLRETSL
• Function: Has guanylyl cyclase on binding to the beta-1 subunit.; Isoform 2 acts as a negative regulator of guanylyl cyclase activity as it forms non-functional heterodimers with the beta subunits.
• Tissue Specificity: Isoform 1 is expressed in fetal brain, liver, colon, endothelium and testis. Isoform 2 is expressed only in liver, colon and endothelium.
• 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

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Definitive	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Colorectal neoplasm	DISR1UCN	Disputed	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Guanylate cyclase soluble subunit alpha-2 (GUCY1A2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Guanylate cyclase soluble subunit alpha-2 (GUCY1A2).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Guanylate cyclase soluble subunit alpha-2 (GUCY1A2).	[6]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Guanylate cyclase soluble subunit alpha-2 (GUCY1A2).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Guanylate cyclase soluble subunit alpha-2 (GUCY1A2).	[4]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Guanylate cyclase soluble subunit alpha-2 (GUCY1A2).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Guanylate cyclase soluble subunit alpha-2 (GUCY1A2).	[10]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Guanylate cyclase soluble subunit alpha-2 (GUCY1A2).	[11]

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-2 (GUCY1A2).	[9]

References

• [1] Individual common variants exert weak effects on the risk for autism spectrum disorders.Hum Mol Genet. 2012 Nov 1;21(21):4781-92. doi: 10.1093/hmg/dds301. Epub 2012 Jul 26.
• [2] Convergence of mutation and epigenetic alterations identifies common genes in cancer that predict for poor prognosis.PLoS Med. 2008 May 27;5(5):e114. doi: 10.1371/journal.pmed.0050114.
• [3] Genomic and epigenomic integration identifies a prognostic signature in colon cancer.Clin Cancer Res. 2011 Mar 15;17(6):1535-45. doi: 10.1158/1078-0432.CCR-10-2509. Epub 2011 Jan 28.
• [4] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [5] 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.
• [6] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [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] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [11] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.