Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLZO8QS)

• DOT Name: High affinity choline transporter 1 (SLC5A7)
• Synonyms: hCHT1; Hemicholinium-3-sensitive choline transporter; CHT; Solute carrier family 5 member 7
• Gene Name: SLC5A7
• Related Disease:
  Congenital myasthenic syndrome 20
  Neuronopathy, distal hereditary motor, type 7A
  Distal hereditary motor neuropathy type 7
  Obsolete presynaptic congenital myasthenic syndrome
• UniProt ID: SC5A7_HUMAN
• Pfam ID: PF00474
• Sequence:
  MAFHVEGLIAIIVFYLLILLVGIWAAWRTKNSGSAEERSEAIIVGGRDIGLLVGGFTMTA
  TWVGGGYINGTAEAVYVPGYGLAWAQAPIGYSLSLILGGLFFAKPMRSKGYVTMLDPFQQ
  IYGKRMGGLLFIPALMGEMFWAAAIFSALGATISVIIDVDMHISVIISALIATLYTLVGG
  LYSVAYTDVVQLFCIFVGLWISVPFALSHPAVADIGFTAVHAKYQKPWLGTVDSSEVYSW
  LDSFLLLMLGGIPWQAYFQRVLSSSSATYAQVLSFLAAFGCLVMAIPAILIGAIGASTDW
  NQTAYGLPDPKTTEEADMILPIVLQYLCPVYISFFGLGAVSAAVMSSADSSILSASSMFA
  RNIYQLSFRQNASDKEIVWVMRITVFVFGASATAMALLTKTVYGLWYLSSDLVYIVIFPQ
  LLCVLFVKGTNTYGAVAGYVSGLFLRITGGEPYLYLQPLIFYPGYYPDDNGIYNQKFPFK
  TLAMVTSFLTNICISYLAKYLFESGTLPPKLDVFDAVVARHSEENMDKTILVKNENIKLD
  ELALVKPRQSMTLSSTFTNKEAFLDVDSSPEGSGTEDNLQ
• Function: High-affinity Na(+)-coupled choline transmembrane symporter. Functions as an electrogenic, voltage-dependent transporter with variable charge/choline stoichiometry. Choline uptake and choline-induced current is also Cl(-)-dependent where Cl(-) is likely a regulatory ion rather than cotransported ion. Plays a critical role in acetylcholine (ACh) synthesis by taking up the substrate choline from the synaptic cleft into the presynaptic nerve terminals after neurotransmitter release. SLC5A7/CHT1-mediated choline high-affinity transport in cholinergic neurons is the rate-limiting step for production of ACh, thereby facilitating communication by subsequent action potentials. Localized predominantly in presynaptic terminal intracellular organelles, and translocated to the plasma membrane in active form in response to neuronal activity.
• Tissue Specificity: Expressed in putamen, spinal cord and medulla . Expressed in cholinergic neurons .
• KEGG Pathway:
  Cholinergic sy.pse (hsa04725)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  Transport of bile salts and organic acids, metal ions and amine compounds (R-HSA-425366)
  Defective SLC5A7 causes distal hereditary motor neuronopathy 7A (HMN7A) (R-HSA-5619114)
  Defective SLC5A7 causes distal hereditary motor neuronopathy 7A (HMN7A) (R-HSA-5658471)
  Acetylcholine Neurotransmitter Release Cycle (R-HSA-264642)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital myasthenic syndrome 20	DISZ9NC0	Strong	Autosomal recessive	[1]
Neuronopathy, distal hereditary motor, type 7A	DISO2X4K	Strong	Autosomal dominant	[2]
Distal hereditary motor neuropathy type 7	DISJW8SV	Supportive	Autosomal dominant	[2]
Obsolete presynaptic congenital myasthenic syndrome	DISCATK3	Supportive	Autosomal dominant	[3]

4 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 High affinity choline transporter 1 (SLC5A7).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of High affinity choline transporter 1 (SLC5A7).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of High affinity choline transporter 1 (SLC5A7).	[6]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of High affinity choline transporter 1 (SLC5A7).	[7]

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 High affinity choline transporter 1 (SLC5A7).	[8]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] Defective presynaptic choline transport underlies hereditary motor neuropathy. Am J Hum Genet. 2012 Dec 7;91(6):1103-7. doi: 10.1016/j.ajhg.2012.09.019. Epub 2012 Nov 8.
• [3] Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea. Am J Hum Genet. 2016 Sep 1;99(3):753-761. doi: 10.1016/j.ajhg.2016.06.033. Epub 2016 Aug 25.
• [4] 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.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] 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.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] 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.