Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT157TY3)

• DOT Name: Mitochondrial thiamine pyrophosphate carrier (SLC25A19)
• Synonyms: Mitochondrial thiamine pyrophosphate transporter; MTPPT; Mitochondrial uncoupling protein 1; Solute carrier family 25 member 19
• Gene Name: SLC25A19
• Related Disease:
  Amish lethal microcephaly
  Progressive demyelinating neuropathy with bilateral striatal necrosis
  Leigh syndrome
• UniProt ID: TPC_HUMAN
• Pfam ID: PF00153
• Sequence:
  MVGYDPKPDGRNNTKFQVAVAGSVSGLVTRALISPFDVIKIRFQLQHERLSRSDPSAKYH
  GILQASRQILQEEGPTAFWKGHVPAQILSIGYGAVQFLSFEMLTELVHRGSVYDAREFSV
  HFVCGGLAACMATLTVHPVDVLRTRFAAQGEPKVYNTLRHAVGTMYRSEGPQVFYKGLAP
  TLIAIFPYAGLQFSCYSSLKHLYKWAIPAEGKKNENLQNLLCGSGAGVISKTLTYPLDLF
  KKRLQVGGFEHARAAFGQVRRYKGLMDCAKQVLQKEGALGFFKGLSPSLLKAALSTGFMF
  FSYEFFCNVFHCMNRTASQR
• Function: Mitochondrial transporter mediating uptake of thiamine diphosphate into mitochondria. It is not clear if the antiporter activity is affected by the membrane potential or by the proton electrochemical gradient.
• Tissue Specificity: Expressed in all tissues examined except for placenta. Highest levels in colon, kidney, lung, testis, spleen, and brain.
• Reactome Pathway: Vitamin B1 (thiamin) metabolism (R-HSA-196819)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amish lethal microcephaly	DIS4PQYQ	Strong	Autosomal recessive	[1]
Progressive demyelinating neuropathy with bilateral striatal necrosis	DISM391Q	Strong	Autosomal recessive	[1]
Leigh syndrome	DISWQU45	Limited	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Artesunate	DMR27C8	Approved	Mitochondrial thiamine pyrophosphate carrier (SLC25A19) decreases the response to substance of Artesunate.	[15]

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 Mitochondrial thiamine pyrophosphate carrier (SLC25A19).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Mitochondrial thiamine pyrophosphate carrier (SLC25A19).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mitochondrial thiamine pyrophosphate carrier (SLC25A19).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitochondrial thiamine pyrophosphate carrier (SLC25A19).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Mitochondrial thiamine pyrophosphate carrier (SLC25A19).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitochondrial thiamine pyrophosphate carrier (SLC25A19).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mitochondrial thiamine pyrophosphate carrier (SLC25A19).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Mitochondrial thiamine pyrophosphate carrier (SLC25A19).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Mitochondrial thiamine pyrophosphate carrier (SLC25A19).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Mitochondrial thiamine pyrophosphate carrier (SLC25A19).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Mitochondrial thiamine pyrophosphate carrier (SLC25A19).	[12]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Mitochondrial thiamine pyrophosphate carrier (SLC25A19).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Mitochondrial thiamine pyrophosphate carrier (SLC25A19).	[4]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Mitochondrial thiamine pyrophosphate carrier (SLC25A19).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Mitochondrial thiamine pyrophosphate carrier (SLC25A19).	[12]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] 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.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [6] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [13] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] Factors determining sensitivity or resistance of tumor cell lines towards artesunate. Chem Biol Interact. 2010 Apr 15;185(1):42-52.