Details of Drug Off-Target (DOT)

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

• DOT Name: Defensin-6 (DEFA6)
• Synonyms: Defensin, alpha 6
• Gene Name: DEFA6
• Related Disease:
  Advanced cancer
  Colonic neoplasm
  Colorectal carcinoma
  Inflammatory bowel disease
  Crohn disease
  Ulcerative colitis
  Clostridioides difficile infection
• UniProt ID: DEF6_HUMAN
• PDB ID: 1ZMQ; 3QTE
• Pfam ID: PF00323 ; PF00879
• Sequence:
  MRTLTILTAVLLVALQAKAEPLQAEDDPLQAKAYEADAQEQRGANDQDFAVSFAEDASSS
  LRALGSTRAFTCHCRRSCYSTEYSYGTCTVMGINHRFCCL
• Function: Host-defense peptide that contributes to intestinal innate immunity and mediates homeostasis at mucosal surfaces by forming higher-order oligomers that capture bacteria and prevent microbial invasion of the epithelium. After binding to bacterial surface proteins, undergoes ordered self-assembly to form fibril-like nanonets that surround and entangle bacteria and thereby prevent bacterial invasion across the epithelial barrier. Entangles and agglutinates Gram-negative bacteria, such as E.coli, S.typhimurium and Y.enterocolitica, and Gram-positive bacteria such as L.monocytogenes, thereby protecting the intestine against invasion by enteric bacterial pathogens. Blocks adhesion of C.albicans to intestinal epithelial cells and thereby suppresses fungal invasion of epithelial cells and biofilm formation. Under reducing conditions and in an acidic environment similar to the intestinal milieu, exhibits inhibitory activity against anaerobic bacteria such as B.adolescentis, L.acidophilus and B.breve, as well as B.longum and S.thermophilus, possibly by leading to alterations in bacterial cell envelope structures. The disulfide-linked oxidized form exhibits negligible antimicrobial activity against Gram-negative and Gram-positive bacteria, as compared to the enteric defensin DEFA5.
• Tissue Specificity: Expressed in Paneth cells of the small intestine (at protein level).
• KEGG Pathway:
  NOD-like receptor sig.ling pathway (hsa04621)
  Staphylococcus aureus infection (hsa05150)
  Transcriptio.l misregulation in cancer (hsa05202)
• Reactome Pathway:
  Alpha-defensins (R-HSA-1462054)
  Defensins (R-HSA-1461973)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[1]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[3]
Crohn disease	DIS2C5Q8	moderate	Biomarker	[4]
Ulcerative colitis	DIS8K27O	moderate	Biomarker	[5]
Clostridioides difficile infection	DIS1A2OI	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Defensin-6 (DEFA6).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Defensin-6 (DEFA6).	[8]

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 Defensin-6 (DEFA6).	[9]

References

• [1] Defensin alpha 6 (DEFA6) is a prognostic marker in colorectal cancer.Cancer Biomark. 2019;24(4):485-495. doi: 10.3233/CBM-182221.
• [2] Identification of defensin alpha6 as a potential biomarker in colon adenocarcinoma.J Biol Chem. 2005 Mar 4;280(9):8260-5. doi: 10.1074/jbc.M410054200. Epub 2004 Dec 21.
• [3] Bioinformatics analysis reveals transcriptome and microRNA signatures and drug repositioning targets for IBD and other autoimmune diseases.Inflamm Bowel Dis. 2012 Dec;18(12):2315-33. doi: 10.1002/ibd.22958. Epub 2012 Apr 5.
• [4] Reduced Human -defensin 6 in Noninflamed Jejunal Tissue of Patients with Crohn's Disease.Inflamm Bowel Dis. 2016 May;22(5):1119-28. doi: 10.1097/MIB.0000000000000707.
• [5] Altered expression of innate immunity genes in different intestinal sites of children with ulcerative colitis.Dig Liver Dis. 2010 Dec;42(12):848-53. doi: 10.1016/j.dld.2010.04.003. Epub 2010 May 7.
• [6] Activation of REG family proteins in colitis.Scand J Gastroenterol. 2011 Nov;46(11):1316-23. doi: 10.3109/00365521.2011.605463.
• [7] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [8] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [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.