Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZERX04)

• DOT Name: Guanylate cyclase activator 2B (GUCA2B)
• Gene Name: GUCA2B
• Related Disease:
  Benign prostatic hyperplasia
  Adenocarcinoma
  Advanced cancer
  Cardiac failure
  Chronic kidney disease
  Colitis
  Colon cancer
  Colon carcinoma
  Colon polyp
  Colorectal carcinoma
  Congestive heart failure
  End-stage renal disease
  Essential hypertension
  High blood pressure
  Inflammatory bowel disease
  Intestinal obstruction
  Nasal polyp
  Neoplasm
  Nephropathy
  Ulcerative colitis
  Chronic renal failure
  Intestinal disorder
  Nephrotic syndrome
  Obesity
  Secretory diarrhea
• UniProt ID: GUC2B_HUMAN
• PDB ID: 1UYA; 1UYB
• Pfam ID: PF02058
• Sequence:
  MGCRAASGLLPGVAVVLLLLLQSTQSVYIQYQGFRVQLESMKKLSDLEAQWAPSPRLQAQ
  SLLPAVCHHPALPQDLQPVCASQEASSIFKTLRTIANDDCELCVNVACTGCL
• Function: Endogenous activator of intestinal guanylate cyclase. It stimulates this enzyme through the same receptor binding region as the heat-stable enterotoxins. May be a potent physiological regulator of intestinal fluid and electrolyte transport. May be an autocrine/paracrine regulator of intestinal salt and water transport.
• Tissue Specificity: Stomach and intestine.
• Reactome Pathway: Digestion (R-HSA-8935690)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Benign prostatic hyperplasia	DISI3CW2	Definitive	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Cardiac failure	DISDC067	Strong	Biomarker	[4]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[5]
Colitis	DISAF7DD	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Genetic Variation	[7]
Colon carcinoma	DISJYKUO	Strong	Genetic Variation	[7]
Colon polyp	DIS7V594	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[8]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[4]
End-stage renal disease	DISXA7GG	Strong	Biomarker	[5]
Essential hypertension	DIS7WI98	Strong	Biomarker	[9]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[9]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[6]
Intestinal obstruction	DISE52WH	Strong	Biomarker	[10]
Nasal polyp	DISLP3XE	Strong	Altered Expression	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Nephropathy	DISXWP4P	Strong	Biomarker	[12]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[13]
Chronic renal failure	DISGG7K6	Limited	Biomarker	[5]
Intestinal disorder	DISGPMUQ	Limited	Altered Expression	[14]
Nephrotic syndrome	DISSPSC2	Limited	Biomarker	[5]
Obesity	DIS47Y1K	Limited	Altered Expression	[15]
Secretory diarrhea	DISBX8WG	Limited	Biomarker	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Guanylate cyclase activator 2B (GUCA2B).	[16]

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 activator 2B (GUCA2B).	[17]

References

• [1] Occurrence and localization of uroguanylin in the aging human prostate.Histochem Cell Biol. 2003 Jan;119(1):69-76. doi: 10.1007/s00418-002-0490-3. Epub 2002 Dec 21.
• [2] Uroguanylin treatment suppresses polyp formation in the Apc(Min/+) mouse and induces apoptosis in human colon adenocarcinoma cells via cyclic GMP.Cancer Res. 2000 Sep 15;60(18):5151-7.
• [3] Colonic epithelial cell diversity in health and inflammatory bowel disease.Nature. 2019 Mar;567(7746):49-55. doi: 10.1038/s41586-019-0992-y. Epub 2019 Feb 27.
• [4] Uroguanylin: a new actor in the energy balance movie.J Mol Endocrinol. 2018 Feb;60(2):R31-R38. doi: 10.1530/JME-17-0263. Epub 2017 Dec 4.
• [5] Guanylin and uroguanylin regulate electrolyte transport in isolated human cortical collecting ducts.Kidney Int. 2005 Apr;67(4):1420-7. doi: 10.1111/j.1523-1755.2005.00219.x.
• [6] The guanylate cyclase-C signaling pathway is down-regulated in inflammatory bowel disease.Scand J Gastroenterol. 2015;50(10):1241-52. doi: 10.3109/00365521.2015.1038849. Epub 2015 May 15.
• [7] Hybrid Method Based on Information Gain and Support Vector Machine for Gene Selection in Cancer Classification.Genomics Proteomics Bioinformatics. 2017 Dec;15(6):389-395. doi: 10.1016/j.gpb.2017.08.002. Epub 2017 Dec 12.
• [8] Intestinal GUCY2C prevents TGF- secretion coordinating desmoplasia and hyperproliferation in colorectal cancer.Cancer Res. 2013 Nov 15;73(22):6654-66. doi: 10.1158/0008-5472.CAN-13-0887. Epub 2013 Oct 1.
• [9] Haplotype-based case-control study of the association between the guanylate cyclase activator 2B (GUCA2B, Uroguanylin) gene and essential hypertension.Hypertens Res. 2007 Sep;30(9):789-96. doi: 10.1291/hypres.30.789.
• [10] Synthesis of phenylpyrimidinones as guanylyl cyclase C inhibitors.Pharmazie. 2019 Jan 1;74(1):15-17. doi: 10.1691/ph.2019.8775.
• [11] Expression of guanylin and uroguanylin mRNA in human nasal mucosa and nasal polyps.Acta Otolaryngol. 2004 Mar;124(2):179-85. doi: 10.1080/00016480310016073.
• [12] Guanylate Cyclase C: A Current Hot Target, from Physiology to Pathology.Curr Med Chem. 2018;25(16):1879-1908. doi: 10.2174/0929867325666171205150310.
• [13] Expression of guanylate cyclase-C, guanylin, and uroguanylin is downregulated proportionally to the ulcerative colitis disease activity index.Sci Rep. 2016 Apr 29;6:25034. doi: 10.1038/srep25034.
• [14] Guanylin regulatory peptides: structures, biological activities mediated by cyclic GMP and pathobiology.Regul Pept. 1999 May 31;81(1-3):25-39. doi: 10.1016/s0167-0115(99)00033-6.
• [15] Immunohistochemical Staining for Uroguanylin, a Satiety Hormone, is Decreased in Intestinal Tissue Specimens From Female Adolescents With Obesity.Pediatr Dev Pathol. 2018 May-Jun;21(3):285-295. doi: 10.1177/1093526617722912. Epub 2017 Aug 29.
• [16] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [17] 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.