Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHRUON2)

• DOT Name: Sodium- and chloride-dependent glycine transporter 1 (SLC6A9)
• Synonyms: GlyT-1; GlyT1; Solute carrier family 6 member 9
• Gene Name: SLC6A9
• Related Disease:
  Atypical glycine encephalopathy
  Infantile glycine encephalopathy
• UniProt ID: SC6A9_HUMAN
• PDB ID: 6ZBV; 6ZPL
• Pfam ID: PF00209
• Sequence:
  MSGGDTRAAIARPRMAAAHGPVAPSSPEQVTLLPVQRSFFLPPFSGATPSTSLAESVLKV
  WHGAYNSGLLPQLMAQHSLAMAQNGAVPSEATKRDQNLKRGNWGNQIEFVLTSVGYAVGL
  GNVWRFPYLCYRNGGGAFMFPYFIMLIFCGIPLFFMELSFGQFASQGCLGVWRISPMFKG
  VGYGMMVVSTYIGIYYNVVICIAFYYFFSSMTHVLPWAYCNNPWNTHDCAGVLDASNLTN
  GSRPAALPSNLSHLLNHSLQRTSPSEEYWRLYVLKLSDDIGNFGEVRLPLLGCLGVSWLV
  VFLCLIRGVKSSGKVVYFTATFPYVVLTILFVRGVTLEGAFDGIMYYLTPQWDKILEAKV
  WGDAASQIFYSLGCAWGGLITMASYNKFHNNCYRDSVIISITNCATSVYAGFVIFSILGF
  MANHLGVDVSRVADHGPGLAFVAYPEALTLLPISPLWSLLFFFMLILLGLGTQFCLLETL
  VTAIVDEVGNEWILQKKTYVTLGVAVAGFLLGIPLTSQAGIYWLLLMDNYAASFSLVVIS
  CIMCVAIMYIYGHRNYFQDIQMMLGFPPPLFFQICWRFVSPAIIFFILVFTVIQYQPITY
  NHYQYPGWAVAIGFLMALSSVLCIPLYAMFRLCRTDGDTLLQRLKNATKPSRDWGPALLE
  HRTGRYAPTIAPSPEDGFEVQPLHPDKAQIPIVGSNGSSRLQDSRI
• Function: Sodium- and chloride-dependent glycine transporter. Essential for regulating glycine concentrations at inhibitory glycinergic synapses; [Isoform GlyT-1B]: Sodium- and chloride-dependent glycine transporter; [Isoform GlyT-1C]: Sodium- and chloride-dependent glycine transporter.
• Tissue Specificity: .Expressed in the brain, kidney, pancreas, lung, placenta and liver.; [Isoform GlyT-1B]: Expressed in the brain, kidney, pancreas, lung, placenta and liver.; [Isoform GlyT-1C]: Expressed only in the brain.
• KEGG Pathway: Sy.ptic vesicle cycle (hsa04721)
• Reactome Pathway: Na+/Cl- dependent neurotransmitter transporters (R-HSA-442660)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atypical glycine encephalopathy	DIS9KV6Z	Strong	Autosomal recessive	[1]
Infantile glycine encephalopathy	DISLOECI	Supportive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methamphetamine	DMPM4SK	Approved	Sodium- and chloride-dependent glycine transporter 1 (SLC6A9) increases the response to substance of Methamphetamine.	[18]

23 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 Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[2]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[6]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[7]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[8]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[2]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[2]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[9]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[2]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[2]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[2]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil decreases the expression of Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[2]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[10]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[13]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[14]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[15]
Nobiletin	DM7R3B6	Preclinical	Nobiletin increases the expression of Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[17]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Sodium- and chloride-dependent glycine transporter 1 (SLC6A9).	[5]

References

• [1] Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans. Hum Genet. 2016 Nov;135(11):1263-1268.
• [2] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [3] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [4] 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.
• [5] 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.
• [6] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [7] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [8] Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1. Redox Biol. 2020 Jan;28:101321. doi: 10.1016/j.redox.2019.101321. Epub 2019 Sep 5.
• [9] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [12] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [13] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [14] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [15] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [16] Characteristics of nobiletin-mediated alteration of gene expression in cultured cell lines. Biochem Biophys Res Commun. 2013 Feb 15;431(3):530-4.
• [17] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [18] The glycine transporter 1 gene (GLYT1) is associated with methamphetamine-use disorder. Am J Med Genet B Neuropsychiatr Genet. 2008 Jan 5;147B(1):54-8. doi: 10.1002/ajmg.b.30565.