Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOQWE4C)

• DOT Name: Defensin alpha 4 (DEFA4)
• Synonyms: Corticostatin HP-4; HNP-4; HP-4; Neutrophil defensin 4
• Gene Name: DEFA4
• Related Disease:
  Meningococcal disease
  Microscopic polyangiitis
  Periodontitis
• UniProt ID: DEF4_HUMAN
• PDB ID: 1ZMM; 6DMM; 6DMQ
• Pfam ID: PF00323 ; PF00879
• Sequence:
  MRIIALLAAILLVALQVRAGPLQARGDEAPGQEQRGPEDQDISISFAWDKSSALQVSGST
  RGMVCSCRLVFCRRTELRVGNCLIGGVSFTYCCTRVD
• Function: Host-defense peptide that has antimicrobial activity against Gram-negative bacteria, and to a lesser extent also against Gram-positive bacteria and fungi. Exhibits antimicrobial activity against Gram-negative E.coli and E.aerogenes and Gram-positive S.faecalis, S.aureus and B.cereus and the yeast C.albicans (in vitro). Interacts with pathogenic surface proteins and toxins, such as HIV-1 surface protein gp120 and B.anthracis anthrax lethal factor lef. Protects blood cells against infection with HIV-1 (in vitro). Inhibits enzymatic activity of B.anthracis lef/anthrax lethal factor (in vitro). Inhibits corticotropin (ACTH)-stimulated corticosterone production (in vitro).
• Tissue Specificity: Expressed in neutrophils (at protein level) . Expressed in bone marrow .
• 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)
  Neutrophil degranulation (R-HSA-6798695)
  Defensins (R-HSA-1461973)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Meningococcal disease	DISGDM2Z	Limited	Biomarker	[1]
Microscopic polyangiitis	DIS74KSO	Limited	Biomarker	[2]
Periodontitis	DISI9JOI	Limited	Altered Expression	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Defensin alpha 4 (DEFA4).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Defensin alpha 4 (DEFA4).	[7]

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 alpha 4 (DEFA4).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Defensin alpha 4 (DEFA4).	[6]

References

• [1] Polymorphisms in PARP, IL1B, IL4, IL10, C1INH, DEFB1, and DEFA4 in meningococcal disease in three populations.Shock. 2010 Jul;34(1):17-22. doi: 10.1097/SHK.0b013e3181ce2c7d.
• [2] Prediction of response to remission induction therapy by gene expression profiling of peripheral blood in Japanese patients with microscopic polyangiitis.Arthritis Res Ther. 2017 May 31;19(1):117. doi: 10.1186/s13075-017-1328-7.
• [3] Antimicrobial peptide gene expression in periodontitis patients: A pilot study.J Clin Periodontol. 2018 May;45(5):524-537. doi: 10.1111/jcpe.12879. Epub 2018 Mar 23.
• [4] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [5] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [6] Role of NADPH oxidase in arsenic-induced reactive oxygen species formation and cytotoxicity in myeloid leukemia cells. Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4578-83.
• [7] 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.