Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT46R03O)

• DOT Name: Choline transporter-like protein 1 (SLC44A1)
• Synonyms: CDw92; Solute carrier family 44 member 1; CD antigen CD92
• Gene Name: SLC44A1
• Related Disease: Neurodegeneration, childhood-onset, with ataxia, tremor, optic atrophy, and cognitive decline
• UniProt ID: CTL1_HUMAN
• PDB ID: 7WWB
• Pfam ID: PF04515
• Sequence:
  MGCCSSASSAAQSSKREWKPLEDRSCTDIPWLLLFILFCIGMGFICGFSIATGAAARLVS
  GYDSYGNICGQKNTKLEAIPNSGMDHTQRKYVFFLDPCNLDLINRKIKSVALCVAACPRQ
  ELKTLSDVQKFAEINGSALCSYNLKPSEYTTSPKSSVLCPKLPVPASAPIPFFHRCAPVN
  ISCYAKFAEALITFVSDNSVLHRLISGVMTSKEIILGLCLLSLVLSMILMVIIRYISRVL
  VWILTILVILGSLGGTGVLWWLYAKQRRSPKETVTPEQLQIAEDNLRALLIYAISATVFT
  VILFLIMLVMRKRVALTIALFHVAGKVFIHLPLLVFQPFWTFFALVLFWVYWIMTLLFLG
  TTGSPVQNEQGFVEFKISGPLQYMWWYHVVGLIWISEFILACQQMTVAGAVVTYYFTRDK
  RNLPFTPILASVNRLIRYHLGTVAKGSFIITLVKIPRMILMYIHSQLKGKENACARCVLK
  SCICCLWCLEKCLNYLNQNAYTATAINSTNFCTSAKDAFVILVENALRVATINTVGDFML
  FLGKVLIVCSTGLAGIMLLNYQQDYTVWVLPLIIVCLFAFLVAHCFLSIYEMVVDVLFLC
  FAIDTKYNDGSPGREFYMDKVLMEFVENSRKAMKEAGKGGVADSRELKPMASGASSA
• Function: Choline/H+ antiporter. Also acts as a high-affinity ethanolamine/H+ antiporter, regulating the supply of extracellular ethanolamine (Etn) for the CDP-Etn pathway, redistribute intracellular Etn and balance the CDP-Cho and CDP-Etn arms of the Kennedy pathway. Involved in membrane synthesis and myelin production.
• Tissue Specificity: Expressed in various cells of the hematopoietic system.
• KEGG Pathway: Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  Transport of bile salts and organic acids, metal ions and amine compounds (R-HSA-425366)
  Choline catabolism (R-HSA-6798163)
  Synthesis of PC (R-HSA-1483191)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodegeneration, childhood-onset, with ataxia, tremor, optic atrophy, and cognitive decline	DISVXFH2	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Choline transporter-like protein 1 (SLC44A1).	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Choline transporter-like protein 1 (SLC44A1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Choline transporter-like protein 1 (SLC44A1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Choline transporter-like protein 1 (SLC44A1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Choline transporter-like protein 1 (SLC44A1).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Choline transporter-like protein 1 (SLC44A1).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Choline transporter-like protein 1 (SLC44A1).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Choline transporter-like protein 1 (SLC44A1).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Choline transporter-like protein 1 (SLC44A1).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Choline transporter-like protein 1 (SLC44A1).	[10]

References

• [1] Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders. JAMA Psychiatry. 2017 Mar 1;74(3):293-299. doi: 10.1001/jamapsychiatry.2016.3798.
• [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] Evidence for a role of claudin 2 as a proximal tubular stress responsive paracellular water channel. Toxicol Appl Pharmacol. 2014 Sep 1;279(2):163-72.
• [4] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [8] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [9] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [10] 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.