Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAWGR4K)

• DOT Name: Solute carrier family 25 member 3 (SLC25A3)
• Synonyms: Phosphate carrier protein, mitochondrial; Phosphate transport protein; PTP
• Gene Name: SLC25A3
• Related Disease:
  Cardiomyopathy-hypotonia-lactic acidosis syndrome
  Mitochondrial disease
• UniProt ID: S25A3_HUMAN
• Pfam ID: PF00153
• Sequence:
  MFSSVAHLARANPFNTPHLQLVHDGLGDLRSSSPGPTGQPRRPRNLAAAAVEEQYSCDYG
  SGRFFILCGLGGIISCGTTHTALVPLDLVKCRMQVDPQKYKGIFNGFSVTLKEDGVRGLA
  KGWAPTFLGYSMQGLCKFGFYEVFKVLYSNMLGEENTYLWRTSLYLAASASAEFFADIAL
  APMEAAKVRIQTQPGYANTLRDAAPKMYKEEGLKAFYKGVAPLWMRQIPYTMMKFACFER
  TVEALYKFVVPKPRSECSKPEQLVVTFVAGYIAGVFCAIVSHPADSVVSVLNKEKGSSAS
  LVLKRLGFKGVWKGLFARIIMIGTLTALQWFIYDSVKVYFRLPRPPPPEMPESLKKKLGL
  TQ
• Function: Inorganic ion transporter that transports phosphate or copper ions across the mitochondrial inner membrane into the matrix compartment. Mediates proton-coupled symport of phosphate ions necessary for mitochondrial oxidative phosphorylation of ADP to ATP. Transports copper ions probably in the form of anionic copper(I) complexes to maintain mitochondrial matrix copper pool and to supply copper for cytochrome C oxidase complex assembly. May also play a role in regulation of the mitochondrial permeability transition pore (mPTP).

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiomyopathy-hypotonia-lactic acidosis syndrome	DISN4IMT	Strong	Autosomal recessive	[1]
Mitochondrial disease	DISKAHA3	Moderate	Autosomal recessive	[2]

3 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 Solute carrier family 25 member 3 (SLC25A3).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Solute carrier family 25 member 3 (SLC25A3).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Solute carrier family 25 member 3 (SLC25A3).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Solute carrier family 25 member 3 (SLC25A3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Solute carrier family 25 member 3 (SLC25A3).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Solute carrier family 25 member 3 (SLC25A3).	[6]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Solute carrier family 25 member 3 (SLC25A3).	[7]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Solute carrier family 25 member 3 (SLC25A3).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Solute carrier family 25 member 3 (SLC25A3).	[11]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Solute carrier family 25 member 3 (SLC25A3).	[12]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Solute carrier family 25 member 3 (SLC25A3).	[13]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Solute carrier family 25 member 3 (SLC25A3).	[14]
biochanin A	DM0HPWY	Investigative	biochanin A decreases the expression of Solute carrier family 25 member 3 (SLC25A3).	[15]

References

• [1] Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation. Am J Hum Genet. 2007 Mar;80(3):478-84. doi: 10.1086/511788. Epub 2007 Jan 10.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] 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.
• [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] 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.
• [9] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [10] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [12] Lipid Rafts Disruption Increases Ochratoxin A Cytotoxicity to Hepatocytes. J Biochem Mol Toxicol. 2016 Feb;30(2):71-9. doi: 10.1002/jbt.21738. Epub 2015 Aug 25.
• [13] Alteration of estrogen-regulated gene expression in human cells induced by the agricultural and horticultural herbicide glyphosate. Hum Exp Toxicol. 2007 Sep;26(9):747-52. doi: 10.1177/0960327107083453.
• [14] 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.
• [15] Mechanisms of the growth inhibitory effects of the isoflavonoid biochanin A on LNCaP cells and xenografts. Prostate. 2002 Aug 1;52(3):201-12.