Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHYISW6)

• DOT Name: Guanylyl cyclase C (GUCY2C)
• Synonyms: GC-C; EC 4.6.1.2; Heat-stable enterotoxin receptor; STA receptor; hSTAR; Intestinal guanylate cyclase
• Gene Name: GUCY2C
• Related Disease:
  Congenital diarrhea 6
  Intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency
  Congenital sodium diarrhea
• UniProt ID: GUC2C_HUMAN
• PDB ID: 8FX4; 8GHO; 8GHP
• EC Number: 4.6.1.2
• Pfam ID: PF00211 ; PF07714
• Sequence:
  MKTLLLDLALWSLLFQPGWLSFSSQVSQNCHNGSYEISVLMMGNSAFAEPLKNLEDAVNE
  GLEIVRGRLQNAGLNVTVNATFMYSDGLIHNSGDCRSSTCEGLDLLRKISNAQRMGCVLI
  GPSCTYSTFQMYLDTELSYPMISAGSFGLSCDYKETLTRLMSPARKLMYFLVNFWKTNDL
  PFKTYSWSTSYVYKNGTETEDCFWYLNALEASVSYFSHELGFKVVLRQDKEFQDILMDHN
  RKSNVIIMCGGPEFLYKLKGDRAVAEDIVIILVDLFNDQYFEDNVTAPDYMKNVLVLTLS
  PGNSLLNSSFSRNLSPTKRDFALAYLNGILLFGHMLKIFLENGENITTPKFAHAFRNLTF
  EGYDGPVTLDDWGDVDSTMVLLYTSVDTKKYKVLLTYDTHVNKTYPVDMSPTFTWKNSKL
  PNDITGRGPQILMIAVFTLTGAVVLLLLVALLMLRKYRKDYELRQKKWSHIPPENIFPLE
  TNETNHVSLKIDDDKRRDTIQRLRQCKYDKKRVILKDLKHNDGNFTEKQKIELNKLLQID
  YYNLTKFYGTVKLDTMIFGVIEYCERGSLREVLNDTISYPDGTFMDWEFKISVLYDIAKG
  MSYLHSSKTEVHGRLKSTNCVVDSRMVVKITDFGCNSILPPKKDLWTAPEHLRQANISQK
  GDVYSYGIIAQEIILRKETFYTLSCRDRNEKIFRVENSNGMKPFRPDLFLETAEEKELEV
  YLLVKNCWEEDPEKRPDFKKIETTLAKIFGLFHDQKNESYMDTLIRRLQLYSRNLEHLVE
  ERTQLYKAERDRADRLNFMLLPRLVVKSLKEKGFVEPELYEEVTIYFSDIVGFTTICKYS
  TPMEVVDMLNDIYKSFDHIVDHHDVYKVETIGDAYMVASGLPKRNGNRHAIDIAKMALEI
  LSFMGTFELEHLPGLPIWIRIGVHSGPCAAGVVGIKMPRYCLFGDTVNTASRMESTGLPL
  RIHVSGSTIAILKRTECQFLYEVRGETYLKGRGNETTYWLTGMKDQKFNLPTPPTVENQQ
  RLQAEFSDMIANSLQKRQAAGIRSQKPRRVASYKKGTLEYLQLNTTDKESTYF
• Function: Guanylyl cyclase that catalyzes synthesis of cyclic GMP (cGMP) from GTP. Receptor for the E.coli heat-stable enterotoxin; E.coli enterotoxin markedly stimulates the accumulation of cGMP in mammalian cells expressing GUCY2C. Also activated by the endogenous peptides guanylin and uroguanylin.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Intestinal infectious diseases (R-HSA-8942233)
  Digestion (R-HSA-8935690)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital diarrhea 6	DISL3ZQP	Definitive	Autosomal dominant	[1]
Intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency	DISJK2K0	Definitive	Autosomal recessive	[2]
Congenital sodium diarrhea	DISDXE72	Supportive	Autosomal dominant	[3]

6 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 Guanylyl cyclase C (GUCY2C).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Guanylyl cyclase C (GUCY2C).	[5]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Guanylyl cyclase C (GUCY2C).	[7]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Guanylyl cyclase C (GUCY2C).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Guanylyl cyclase C (GUCY2C).	[4]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Guanylyl cyclase C (GUCY2C).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Guanylyl cyclase C (GUCY2C).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Guanylyl cyclase C (GUCY2C).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Guanylyl cyclase C (GUCY2C).	[10]

References

• [1] Familial diarrhea syndrome caused by an activating GUCY2C mutation. N Engl J Med. 2012 Apr 26;366(17):1586-95. doi: 10.1056/NEJMoa1110132. Epub 2012 Mar 21.
• [2] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [3] Congenital secretory diarrhoea caused by activating germline mutations in GUCY2C. Gut. 2016 Aug;65(8):1306-13. doi: 10.1136/gutjnl-2015-309441. Epub 2015 May 20.
• [4] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [5] 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.
• [6] 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.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] 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.
• [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] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [11] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.