Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNG3HH4)

• DOT Name: Dual oxidase maturation factor 1 (DUOXA1)
• Synonyms: Dual oxidase activator 1; Numb-interacting protein
• Gene Name: DUOXA1
• Related Disease:
  Anemia
  Breast cancer
  Breast carcinoma
  Congenital hypothyroidism
  Adult glioblastoma
  Glioblastoma multiforme
  Lung cancer
  Lung carcinoma
  Pneumonia
• UniProt ID: DOXA1_HUMAN
• PDB ID: 7D3E; 7D3F
• Pfam ID: PF10204
• Sequence:
  MATLGHTFPFYAGPKPTFPMDTTLASIIMIFLTALATFIVILPGIRGKTRLFWLLRVVTS
  LFIGAAILAVNFSSEWSVGQVSTNTSYKAFSSEWISADIGLQVGLGGVNITLTGTPVQQL
  NETINYNEEFTWRLGENYAEEYAKALEKGLPDPVLYLAEKFTPRSPCGLYRQYRLAGHYT
  SAMLWVAFLCWLLANVMLSMPVLVYGGYMLLATGIFQLLALLFFSMATSLTSPCPLHLGA
  SVLHTHHGPAFWITLTTGLLCVLLGLAMAVAHRMQPHRLKAFFNQSVDEDPMLEWSPEEG
  GLLSPRYRSMADSPKSQDIPLSEASSTKAYCKEAHPKDPDCAL
• Function: May be required for the maturation and the transport from the endoplasmic reticulum to the plasma membrane of functional DUOX1.
• Tissue Specificity: Specifically expressed in thyroid gland. Also detected in esophagus.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anemia	DISTVL0C	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Congenital hypothyroidism	DISL5XVU	Strong	Biomarker	[3]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[4]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[4]
Lung cancer	DISCM4YA	Limited	Altered Expression	[5]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[5]
Pneumonia	DIS8EF3M	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Dual oxidase maturation factor 1 (DUOXA1).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Dual oxidase maturation factor 1 (DUOXA1).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Dual oxidase maturation factor 1 (DUOXA1).	[9]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Dual oxidase maturation factor 1 (DUOXA1).	[10]

References

• [1] Efficacy and safety of Everolimus and Exemestane in hormone-receptor positive (HR+) human-epidermal-growth-factor negative (HER2-) advanced breast cancer patients: New insights beyond clinical trials. The EVA study.Breast. 2017 Oct;35:115-121. doi: 10.1016/j.breast.2017.06.043. Epub 2017 Jul 13.
• [2] NIP1/DUOXA1 expression in epithelial breast cancer cells: regulation of cell adhesion and actin dynamics.Breast Cancer Res Treat. 2010 Feb;119(3):773-86. doi: 10.1007/s10549-009-0372-7. Epub 2009 Mar 26.
• [3] Identification of Two Missense Mutations in DUOX1 (p.R1307Q) and DUOXA1 (p.R56W) That Can Cause Congenital Hypothyroidism Through Impairing H(2)O(2) Generation.Front Endocrinol (Lausanne). 2019 Aug 2;10:526. doi: 10.3389/fendo.2019.00526. eCollection 2019.
• [4] Amplification and expression of splice variants of the gene encoding the P450 cytochrome 25-hydroxyvitamin D(3) 1,alpha-hydroxylase (CYP 27B1) in human malignant glioma.Clin Cancer Res. 2001 Apr;7(4):868-75.
• [5] Silencing of DUOX NADPH oxidases by promoter hypermethylation in lung cancer.Cancer Res. 2008 Feb 15;68(4):1037-45. doi: 10.1158/0008-5472.CAN-07-5782.
• [6] Indirect (herd) protection, following pneumococcal conjugated vaccines introduction: A systematic review of the literature.Vaccine. 2017 May 19;35(22):2882-2891. doi: 10.1016/j.vaccine.2017.04.032. Epub 2017 Apr 24.
• [7] 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.
• [8] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [9] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [10] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.