Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT04I3OW)

• DOT Name: Sodium-dependent neutral amino acid transporter B(0)AT1 (SLC6A19)
• Synonyms: Solute carrier family 6 member 19; System B(0) neutral amino acid transporter AT1
• Gene Name: SLC6A19
• Related Disease: Hartnup disease
• UniProt ID: S6A19_HUMAN
• PDB ID: 6M17; 6M18; 6M1D; 7DWX; 7V61; 8I92; 8I93
• Pfam ID: PF00209
• Sequence:
  MVRLVLPNPGLDARIPSLAELETIEQEEASSRPKWDNKAQYMLTCLGFCVGLGNVWRFPY
  LCQSHGGGAFMIPFLILLVLEGIPLLYLEFAIGQRLRRGSLGVWSSIHPALKGLGLASML
  TSFMVGLYYNTIISWIMWYLFNSFQEPLPWSDCPLNENQTGYVDECARSSPVDYFWYRET
  LNISTSISDSGSIQWWMLLCLACAWSVLYMCTIRGIETTGKAVYITSTLPYVVLTIFLIR
  GLTLKGATNGIVFLFTPNVTELAQPDTWLDAGAQVFFSFSLAFGGLISFSSYNSVHNNCE
  KDSVIVSIINGFTSVYVAIVVYSVIGFRATQRYDDCFSTNILTLINGFDLPEGNVTQENF
  VDMQQRCNASDPAAYAQLVFQTCDINAFLSEAVEGTGLAFIVFTEAITKMPLSPLWSVLF
  FIMLFCLGLSSMFGNMEGVVVPLQDLRVIPPKWPKEVLTGLICLGTFLIGFIFTLNSGQY
  WLSLLDSYAGSIPLLIIAFCEMFSVVYVYGVDRFNKDIEFMIGHKPNIFWQVTWRVVSPL
  LMLIIFLFFFVVEVSQELTYSIWDPGYEEFPKSQKISYPNWVYVVVVIVAGVPSLTIPGY
  AIYKLIRNHCQKPGDHQGLVSTLSTASMNGDLKY
• Function: Transporter that mediates resorption of neutral amino acids across the apical membrane of renal and intestinal epithelial cells. This uptake is sodium-dependent and chloride-independent. Requires CLTRN in kidney or ACE2 in intestine for cell surface expression and amino acid transporter activity.
• Tissue Specificity: Robust expression in kidney and small intestine, with minimal expression in pancreas . Also expressed in stomach, liver, duodenum, ileocecum, colon and prostate. Not detected in testis, whole brain, cerebellum, fetal liver, spleen, skeletal muscle, uterus, heart or lung.
• KEGG Pathway:
  Protein digestion and absorption (hsa04974)
  Mineral absorption (hsa04978)
• Reactome Pathway:
  Na+/Cl- dependent neurotransmitter transporters (R-HSA-442660)
  Defective SLC6A19 causes Hartnup disorder (HND) (R-HSA-5619044)
  Defective SLC6A19 causes Hartnup disorder (HND) (R-HSA-5659735)
  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
Hartnup disease	DISYK0UH	Definitive	Autosomal recessive	[1]

4 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 Sodium-dependent neutral amino acid transporter B(0)AT1 (SLC6A19).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Sodium-dependent neutral amino acid transporter B(0)AT1 (SLC6A19).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Sodium-dependent neutral amino acid transporter B(0)AT1 (SLC6A19).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Sodium-dependent neutral amino acid transporter B(0)AT1 (SLC6A19).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Sodium-dependent neutral amino acid transporter B(0)AT1 (SLC6A19).	[4]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Sodium-dependent neutral amino acid transporter B(0)AT1 (SLC6A19).	[5]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Sodium-dependent neutral amino acid transporter B(0)AT1 (SLC6A19).	[6]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [5] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [6] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [7] 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.
• [8] 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.