Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1HIORM)

• DOT Name: Choline transporter-like protein 4 (SLC44A4)
• Synonyms: Solute carrier family 44 member 4; Thiamine pyrophosphate transporter 1; hTPPT1
• Gene Name: SLC44A4
• Related Disease:
  Autosomal dominant nonsyndromic hearing loss
  Hearing loss, autosomal dominant 72
  Nonsyndromic genetic hearing loss
• UniProt ID: CTL4_HUMAN
• Pfam ID: PF04515
• Sequence:
  MGGKQRDEDDEAYGKPVKYDPSFRGPIKNRSCTDVICCVLFLLFILGYIVVGIVAWLYGD
  PRQVLYPRNSTGAYCGMGENKDKPYLLYFNIFSCILSSNIISVAENGLQCPTPQVCVSSC
  PEDPWTVGKNEFSQTVGEVFYTKNRNFCLPGVPWNMTVITSLQQELCPSFLLPSAPALGR
  CFPWTNVTPPALPGITNDTTIQQGISGLIDSLNARDISVKIFEDFAQSWYWILVALGVAL
  VLSLLFILLLRLVAGPLVLVLILGVLGVLAYGIYYCWEEYRVLRDKGASISQLGFTTNLS
  AYQSVQETWLAALIVLAVLEAILLLMLIFLRQRIRIAIALLKEASKAVGQMMSTMFYPLV
  TFVLLLICIAYWAMTALYLATSGQPQYVLWASNISSPGCEKVPINTSCNPTAHLVNSSCP
  GLMCVFQGYSSKGLIQRSVFNLQIYGVLGLFWTLNWVLALGQCVLAGAFASFYWAFHKPQ
  DIPTFPLISAFIRTLRYHTGSLAFGALILTLVQIARVILEYIDHKLRGVQNPVARCIMCC
  FKCCLWCLEKFIKFLNRNAYIMIAIYGKNFCVSAKNAFMLLMRNIVRVVVLDKVTDLLLF
  FGKLLVVGGVGVLSFFFFSGRIPGLGKDFKSPHLNYYWLPIMTSILGAYVIASGFFSVFG
  MCVDTLFLCFLEDLERNNGSLDRPYYMSKSLLKILGKKNEAPPDNKKRKK
• Function: Choline transporter that plays a role in the choline-acetylcholine system and is required to the efferent innervation of hair cells in the olivocochlear bundle for the maintenance of physiological function of outer hair cells and the protection of hair cells from acoustic injury. Also described as a thiamine pyrophosphate transporter in colon, may mediate the absorption of microbiota-generated thiamine pyrophosphate and contribute to host thiamine (vitamin B1) homeostasis ; [Isoform 3]: Has also thiamine pyrophosphate transporter activity.
• Tissue Specificity: Highly expressed in colon, also detected in prostate, trachea and lung . Isoform 3 is also expressed in colon but a lower levels .; [Isoform 3]: Expressed in colon at low levels.
• KEGG Pathway: Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  Transport of bile salts and organic acids, metal ions and amine compounds (R-HSA-425366)
  Synthesis of PC (R-HSA-1483191)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant nonsyndromic hearing loss	DISYC1G0	Supportive	Autosomal dominant	[1]
Hearing loss, autosomal dominant 72	DISTAS5Z	Limited	Autosomal dominant	[1]
Nonsyndromic genetic hearing loss	DISZX61P	Limited	Autosomal dominant	[2]

8 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 4 (SLC44A4).	[3]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Choline transporter-like protein 4 (SLC44A4).	[4]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Choline transporter-like protein 4 (SLC44A4).	[5]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Choline transporter-like protein 4 (SLC44A4).	[5]
Selenium	DM25CGV	Approved	Selenium increases the expression of Choline transporter-like protein 4 (SLC44A4).	[6]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Choline transporter-like protein 4 (SLC44A4).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Choline transporter-like protein 4 (SLC44A4).	[8]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Choline transporter-like protein 4 (SLC44A4).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Choline transporter-like protein 4 (SLC44A4).	[9]

References

• [1] SLC44A4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss. Hum Mol Genet. 2017 Jan 15;26(2):383-394.
• [2] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [5] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [6] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [7] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] 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.
• [10] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.