Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP4WXFU)

• DOT Name: Mitochondrial glycine transporter (SLC25A38)
• Synonyms: Appoptosin; Mitochondrial glycine transporter GlyC; Solute carrier family 25 member 38
• Gene Name: SLC25A38
• Related Disease:
  Sideroblastic anemia 2
  Autosomal recessive sideroblastic anemia
• UniProt ID: S2538_HUMAN
• Pfam ID: PF00153
• Sequence:
  MIQNSRPSLLQPQDVGDTVETLMLHPVIKAFLCGSISGTCSTLLFQPLDLLKTRLQTLQP
  SDHGSRRVGMLAVLLKVVRTESLLGLWKGMSPSIVRCVPGVGIYFGTLYSLKQYFLRGHP
  PTALESVMLGVGSRSVAGVCMSPITVIKTRYESGKYGYESIYAALRSIYHSEGHRGLFSG
  LTATLLRDAPFSGIYLMFYNQTKNIVPHDQVDATLIPITNFSCGIFAGILASLVTQPADV
  IKTHMQLYPLKFQWIGQAVTLIFKDYGLRGFFQGGIPRALRRTLMAAMAWTVYEEMMAKM
  GLKS
• Function: Mitochondrial glycine transporter that imports glycine into the mitochondrial matrix. Plays an important role in providing glycine for the first enzymatic step in heme biosynthesis, the condensation of glycine with succinyl-CoA to produce 5-aminolevulinate (ALA) in the mitochondrial matrix. Required during erythropoiesis; Plays a role as pro-apoptotic protein that induces caspase-dependent apoptosis.
• Tissue Specificity: Preferentially expressed in erythroid cells.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Sideroblastic anemia 2	DIS3T984	Definitive	Autosomal recessive	[1]
Autosomal recessive sideroblastic anemia	DIS04G9O	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Mitochondrial glycine transporter (SLC25A38).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mitochondrial glycine transporter (SLC25A38).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitochondrial glycine transporter (SLC25A38).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Mitochondrial glycine transporter (SLC25A38).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Mitochondrial glycine transporter (SLC25A38).	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Mitochondrial glycine transporter (SLC25A38).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mitochondrial glycine transporter (SLC25A38).	[9]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Mitochondrial glycine transporter (SLC25A38).	[10]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia. Nat Genet. 2009 Jun;41(6):651-3. doi: 10.1038/ng.359. Epub 2009 May 3.
• [3] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [9] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [10] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.