Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU1GZOY)

• DOT Name: Transmembrane protein 199 (TMEM199)
• Gene Name: TMEM199
• Related Disease:
  Breast cancer
  Breast carcinoma
  Developmental and epileptic encephalopathy, 36
  Fatty liver disease
  Invasive candidiasis
  TMEM199-CDG
• UniProt ID: TM199_HUMAN
• Pfam ID: PF11712
• Sequence:
  MASSLLAGERLVRALGPGGELEPERLPRKLRAELEAALGKKHKGGDSSSGPQRLVSFRLI
  RDLHQHLRERDSKLYLHELLEGSEIYLPEVVKPPRNPELVARLEKIKIQLANEEYKRITR
  NVTCQDTRHGGTLSDLGKQVRSLKALVITIFNFIVTVVAAFVCTYLGSQYIFTEMASRVL
  AALIVASVVGLAELYVMVRAMEGELGEL
• Function: Accessory component of the proton-transporting vacuolar (V)-ATPase protein pump involved in intracellular iron homeostasis. In aerobic conditions, required for intracellular iron homeostasis, thus triggering the activity of Fe(2+) prolyl hydroxylase (PHD) enzymes, and leading to HIF1A hydroxylation and subsequent proteasomal degradation. Necessary for endolysosomal acidification and lysosomal degradation. May be involved in Golgi homeostasis. Binds 20(S)-hydroxycholesterol (20(S)-OHC).

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Developmental and epileptic encephalopathy, 36	DISG4MY5	Strong	Biomarker	[2]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[2]
Invasive candidiasis	DIS5EI0L	Strong	Biomarker	[3]
TMEM199-CDG	DISFXAD6	Strong	Autosomal recessive	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Transmembrane protein 199 (TMEM199) affects the response to substance of Acetaminophen.	[10]

5 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 Transmembrane protein 199 (TMEM199).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transmembrane protein 199 (TMEM199).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Transmembrane protein 199 (TMEM199).	[7]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Transmembrane protein 199 (TMEM199).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Transmembrane protein 199 (TMEM199).	[9]

References

• [1] Complex sense-antisense architecture of TNFAIP1/POLDIP2 on 17q11.2 represents a novel transcriptional structural-functional gene module involved in breast cancer progression.BMC Genomics. 2010 Feb 10;11 Suppl 1(Suppl 1):S9. doi: 10.1186/1471-2164-11-S1-S9.
• [2] Three unreported cases of TMEM199-CDG, a rare genetic liver disease with abnormal glycosylation.Orphanet J Rare Dis. 2018 Jan 10;13(1):4. doi: 10.1186/s13023-017-0757-3.
• [3] Vacuolar proton-translocating ATPase is required for antifungal resistance and virulence of Candida glabrata.PLoS One. 2019 Jan 23;14(1):e0210883. doi: 10.1371/journal.pone.0210883. eCollection 2019.
• [4] TMEM199 Deficiency Is a Disorder of Golgi Homeostasis Characterized by Elevated Aminotransferases, Alkaline Phosphatase, and Cholesterol and Abnormal Glycosylation. Am J Hum Genet. 2016 Feb 4;98(2):322-30. doi: 10.1016/j.ajhg.2015.12.011. Epub 2016 Jan 28.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] 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.
• [8] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [9] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [10] Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes. Arch Toxicol. 2016 May;90(5):1103-15. doi: 10.1007/s00204-015-1545-2. Epub 2015 Jun 24.