Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKYC433)

• DOT Name: Sodium- and chloride-dependent glycine transporter 2 (SLC6A5)
• Synonyms: GlyT-2; GlyT2; Solute carrier family 6 member 5
• Gene Name: SLC6A5
• Related Disease:
  Hyperekplexia 1
  Hyperekplexia 3
  Hereditary hyperekplexia
• UniProt ID: SC6A5_HUMAN
• Pfam ID: PF00209
• Sequence:
  MDCSAPKEMNKLPANSPEAAAAQGHPDGPCAPRTSPEQELPAAAAPPPPRVPRSASTGAQ
  TFQSADARACEAERPGVGSCKLSSPRAQAASAALRDLREAQGAQASPPPGSSGPGNALHC
  KIPFLRGPEGDANVSVGKGTLERNNTPVVGWVNMSQSTVVLATDGITSVLPGSVATVATQ
  EDEQGDENKARGNWSSKLDFILSMVGYAVGLGNVWRFPYLAFQNGGGAFLIPYLMMLALA
  GLPIFFLEVSLGQFASQGPVSVWKAIPALQGCGIAMLIISVLIAIYYNVIICYTLFYLFA
  SFVSVLPWGSCNNPWNTPECKDKTKLLLDSCVISDHPKIQIKNSTFCMTAYPNVTMVNFT
  SQANKTFVSGSEEYFKYFVLKISAGIEYPGEIRWPLALCLFLAWVIVYASLAKGIKTSGK
  VVYFTATFPYVVLVILLIRGVTLPGAGAGIWYFITPKWEKLTDATVWKDAATQIFFSLSA
  AWGGLITLSSYNKFHNNCYRDTLIVTCTNSATSIFAGFVIFSVIGFMANERKVNIENVAD
  QGPGIAFVVYPEALTRLPLSPFWAIIFFLMLLTLGLDTMFATIETIVTSISDEFPKYLRT
  HKPVFTLGCCICFFIMGFPMITQGGIYMFQLVDTYAASYALVIIAIFELVGISYVYGLQR
  FCEDIEMMIGFQPNIFWKVCWAFVTPTILTFILCFSFYQWEPMTYGSYRYPNWSMVLGWL
  MLACSVIWIPIMFVIKMHLAPGRFIERLKLVCSPQPDWGPFLAQHRGERYKNMIDPLGTS
  SLGLKLPVKDLELGTQC
• Function: Sodium- and chloride-dependent glycine transporter. Terminates the action of glycine by its high affinity sodium-dependent reuptake into presynaptic terminals. May be responsible for the termination of neurotransmission at strychnine-sensitive glycinergic synapses ; [Isoform 2]: Lacks sodium- and chloride-dependent glycine transporter activity; [Isoform 3]: Lacks sodium- and chloride-dependent glycine transporter activity.
• Tissue Specificity: Expressed in medulla, and to a lesser extent in spinal cord and cerebellum.
• KEGG Pathway: Sy.ptic vesicle cycle (hsa04721)
• Reactome Pathway:
  Defective SLC6A5 causes hyperekplexia 3 (HKPX3) (R-HSA-5619089)
  Na+/Cl- dependent neurotransmitter transporters (R-HSA-442660)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyperekplexia 1	DISRXUL0	Definitive	Autosomal recessive	[1]
Hyperekplexia 3	DISDL1V1	Strong	Autosomal recessive	[2]
Hereditary hyperekplexia	DIS9YXFE	Supportive	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Sodium- and chloride-dependent glycine transporter 2 (SLC6A5).	[4]
Testosterone Undecanoate	DMZO10Y	Approved	Testosterone Undecanoate increases the expression of Sodium- and chloride-dependent glycine transporter 2 (SLC6A5).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Sodium- and chloride-dependent glycine transporter 2 (SLC6A5).	[6]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] 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.
• [3] Hereditary Hyperekplexia Overview. 2007 Jul 31 [updated 2019 Dec 19]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [4] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [5] Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men. Biol Reprod. 2009 Mar;80(3):484-92.
• [6] 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.