Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHRD4XO)

• DOT Name: Sodium- and chloride-dependent transporter XTRP3 (SLC6A20)
• Synonyms: Sodium/imino-acid transporter 1; Solute carrier family 6 member 20; Transporter rB21A homolog
• Gene Name: SLC6A20
• Related Disease: Hyperglycinuria
• UniProt ID: S6A20_HUMAN
• PDB ID: 7Y75; 7Y76; 8I91
• Pfam ID: PF00209
• Sequence:
  MEKARPLWANSLQFVFACISYAVGLGNVWRFPYLCQMYGGGSFLVPYIIMLIVEGMPLLY
  LELAVGQRMRQGSIGAWRTISPYLSGVGVASVVVSFFLSMYYNVINAWAFWYLFHSFQDP
  LPWSVCPLNGNHTGYDEECEKASSTQYFWYRKTLNISPSLQENGGVQWEPALCLLLAWLV
  VYLCILRGTESTGKVVYFTASLPYCVLIIYLIRGLTLHGATNGLMYMFTPKIEQLANPKA
  WINAATQIFFSLGLGFGSLIAFASYNEPSNNCQKHAIIVSLINSFTSIFASIVTFSIYGF
  KATFNYENCLKKVSLLLTNTFDLEDGFLTASNLEQVKGYLASAYPSKYSEMFPQIKNCSL
  ESELDTAVQGTGLAFIVYTEAIKNMEVSQLWSVLYFFMLLMLGIGSMLGNTAAILTPLTD
  SKIISSHLPKEAISGLVCLVNCAIGMVFTMEAGNYWFDIFNDYAATLSLLLIVLVETIAV
  CYVYGLRRFESDLKAMTGRAVSWYWKVMWAGVSPLLIVSLFVFYLSDYILTGTLKYQAWD
  ASQGQLVTKDYPAYALAVIGLLVASSTMCIPLAALGTFVQRRLKRGDADPVA
• Function: Mediates the Na(+)- and Cl(-)-dependent uptake of imino acids such as L-proline, N-methyl-L-proline and pipecolate as well as N-methylated amino acids. Also transports glycine, regulates proline and glycine homeostasis in the brain playing a role in the modulation of NMDAR currents.
• Tissue Specificity: Kidney and small intestine. Expressed in the S3 segment of the proximal tubule. Expressed in neurons .
• Reactome Pathway:
  Na+/Cl- dependent neurotransmitter transporters (R-HSA-442660)
  Variant SLC6A20 contributes towards hyperglycinuria (HG) and iminoglycinuria (IG) (R-HSA-5619101)
  Variant SLC6A20 contributes towards hyperglycinuria (HG) and iminoglycinuria (IG) (R-HSA-5660686)
  Amino acid transport across the plasma membrane (R-HSA-352230)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyperglycinuria	DISL7D0R	Limited	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorothiazide	DMLHESP	Approved	Sodium- and chloride-dependent transporter XTRP3 (SLC6A20) increases the Neutropenia ADR of Chlorothiazide.	[14]

9 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 transporter XTRP3 (SLC6A20).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sodium- and chloride-dependent transporter XTRP3 (SLC6A20).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Sodium- and chloride-dependent transporter XTRP3 (SLC6A20).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Sodium- and chloride-dependent transporter XTRP3 (SLC6A20).	[6]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Sodium- and chloride-dependent transporter XTRP3 (SLC6A20).	[7]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Sodium- and chloride-dependent transporter XTRP3 (SLC6A20).	[8]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Sodium- and chloride-dependent transporter XTRP3 (SLC6A20).	[9]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Sodium- and chloride-dependent transporter XTRP3 (SLC6A20).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Sodium- and chloride-dependent transporter XTRP3 (SLC6A20).	[12]

3 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 transporter XTRP3 (SLC6A20).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Sodium- and chloride-dependent transporter XTRP3 (SLC6A20).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Sodium- and chloride-dependent transporter XTRP3 (SLC6A20).	[13]

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] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [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] 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.
• [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] 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.
• [7] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [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] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [10] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [11] 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.
• [12] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [13] 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.
• [14] Genome-wide association study of chemotherapeutic agent-induced severe neutropenia/leucopenia for patients in Biobank Japan. Cancer Sci. 2013 Aug;104(8):1074-82. doi: 10.1111/cas.12186. Epub 2013 Jun 10.