Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9KAJP7)

• DOT Name: ADP/ATP translocase 3 (SLC25A6)
• Synonyms: ADP,ATP carrier protein 3; ADP,ATP carrier protein, isoform T2; ANT 2; Adenine nucleotide translocator 3; ANT 3; Solute carrier family 25 member 6
• Gene Name: SLC25A6
• UniProt ID: ADT3_HUMAN
• Pfam ID: PF00153
• Sequence:
  MTEQAISFAKDFLAGGIAAAISKTAVAPIERVKLLLQVQHASKQIAADKQYKGIVDCIVR
  IPKEQGVLSFWRGNLANVIRYFPTQALNFAFKDKYKQIFLGGVDKHTQFWRYFAGNLASG
  GAAGATSLCFVYPLDFARTRLAADVGKSGTEREFRGLGDCLVKITKSDGIRGLYQGFSVS
  VQGIIIYRAAYFGVYDTAKGMLPDPKNTHIVVSWMIAQTVTAVAGVVSYPFDTVRRRMMM
  QSGRKGADIMYTGTVDCWRKIFRDEGGKAFFKGAWSNVLRGMGGAFVLVLYDELKKVI
• Function: ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell. Cycles between the cytoplasmic-open state (c-state) and the matrix-open state (m-state): operates by the alternating access mechanism with a single substrate-binding site intermittently exposed to either the cytosolic (c-state) or matrix (m-state) side of the inner mitochondrial membrane. In addition to its ADP:ATP antiporter activity, also involved in mitochondrial uncoupling and mitochondrial permeability transition pore (mPTP) activity. Plays a role in mitochondrial uncoupling by acting as a proton transporter: proton transport uncouples the proton flows via the electron transport chain and ATP synthase to reduce the efficiency of ATP production and cause mitochondrial thermogenesis. Proton transporter activity is inhibited by ADP:ATP antiporter activity, suggesting that SLC25A6/ANT3 acts as a master regulator of mitochondrial energy output by maintaining a delicate balance between ATP production (ADP:ATP antiporter activity) and thermogenesis (proton transporter activity). Proton transporter activity requires free fatty acids as cofactor, but does not transport it. Also plays a key role in mPTP opening, a non-specific pore that enables free passage of the mitochondrial membranes to solutes of up to 1.5 kDa, and which contributes to cell death. It is however unclear if SLC25A6/ANT3 constitutes a pore-forming component of mPTP or regulates it.
• Tissue Specificity: Expressed in erythrocytes (at protein level).
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  Necroptosis (hsa04217)
  Cellular senescence (hsa04218)
  Neutrophil extracellular trap formation (hsa04613)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Influenza A (hsa05164)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Influenza Virus Induced Apoptosis (R-HSA-168277)
  Vpr-mediated induction of apoptosis by mitochondrial outer membrane permeabilization (R-HSA-180897)
  Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane (R-HSA-83936)
  Mitochondrial protein import (R-HSA-1268020)

Molecular Interaction Atlas (MIA) of This DOT

1 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 ADP/ATP translocase 3 (SLC25A6).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ADP/ATP translocase 3 (SLC25A6).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ADP/ATP translocase 3 (SLC25A6).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ADP/ATP translocase 3 (SLC25A6).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of ADP/ATP translocase 3 (SLC25A6).	[5]
Selenium	DM25CGV	Approved	Selenium increases the expression of ADP/ATP translocase 3 (SLC25A6).	[6]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of ADP/ATP translocase 3 (SLC25A6).	[7]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of ADP/ATP translocase 3 (SLC25A6).	[7]
Dopamine	DMPGUCF	Approved	Dopamine increases the expression of ADP/ATP translocase 3 (SLC25A6).	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of ADP/ATP translocase 3 (SLC25A6).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of ADP/ATP translocase 3 (SLC25A6).	[9]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of ADP/ATP translocase 3 (SLC25A6).	[10]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of ADP/ATP translocase 3 (SLC25A6).	[11]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of ADP/ATP translocase 3 (SLC25A6).	[12]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [5] 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.
• [6] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [7] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [8] Mitochondrial proteomics investigation of a cellular model of impaired dopamine homeostasis, an early step in Parkinson's disease pathogenesis. Mol Biosyst. 2014 Jun;10(6):1332-44.
• [9] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [10] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [11] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [12] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.