Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVG1VG0)

• DOT Name: Sodium-dependent lysophosphatidylcholine symporter 1 (MFSD2A)
• Synonyms: NLS1; Sodium-dependent LPC symporter 1; Major facilitator superfamily domain-containing protein 2A; HsMFSD2A; MFSD2a
• Gene Name: MFSD2A
• Related Disease:
  Microcephaly 15, primary, autosomal recessive
  Advanced cancer
  Alzheimer disease
  Amyloidosis
  Colitis
  Familial adenomatous polyposis
  Gastric cancer
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Hyperlipidemia
  Intellectual disability
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Microlissencephaly
  Neu-Laxova syndrome 2
  Stomach cancer
  Ulcerative colitis
  Zika virus infection
  Fetal growth restriction
  Lung adenocarcinoma
  Neoplasm
  Obesity
  Autosomal recessive primary microcephaly
  Isolated congenital microcephaly
  Metastatic malignant neoplasm
• UniProt ID: NLS1_HUMAN
• PDB ID: 7OIX
• Pfam ID: PF13347
• Sequence:
  MAKGEGAESGSAAGLLPTSILQSTERPAQVKKEPKKKKQQLSVCNKLCYALGGAPYQVTG
  CALGFFLQIYLLDVAQKDEEVVFCFSSFQVGPFSASIILFVGRAWDAITDPLVGLCISKS
  PWTCLGRLMPWIIFSTPLAVIAYFLIWFVPDFPHGQTYWYLLFYCLFETMVTCFHVPYSA
  LTMFISTEQTERDSATAYRMTVEVLGTVLGTAIQGQIVGQADTPCFQDLNSSTVASQSAN
  HTHGTTSHRETQKAYLLAAGVIVCIYIICAVILILGVREQREPYEAQQSEPIAYFRGLRL
  VMSHGPYIKLITGFLFTSLAFMLVEGNFVLFCTYTLGFRNEFQNLLLAIMLSATLTIPIW
  QWFLTRFGKKTAVYVGISSAVPFLILVALMESNLIITYAVAVAAGISVAAAFLLPWSMLP
  DVIDDFHLKQPHFHGTEPIFFSFYVFFTKFASGVSLGISTLSLDFAGYQTRGCSQPERVK
  FTLNMLVTMAPIVLILLGLLLFKMYPIDEERRRQNKKALQALRDEASSSGCSETDSTELA
  SIL
• Function: Sodium-dependent lysophosphatidylcholine (LPC) symporter, which plays an essential role for blood-brain barrier formation and function. Specifically expressed in endothelium of the blood-brain barrier of micro-vessels and transports LPC into the brain. Transport of LPC is essential because it constitutes the major mechanism by which docosahexaenoic acid (DHA), an omega-3 fatty acid that is essential for normal brain growth and cognitive function, enters the brain. Transports LPC carrying long-chain fatty acids such LPC oleate and LPC palmitate with a minimum acyl chain length of 14 carbons. Does not transport docosahexaenoic acid in unesterified fatty acid. Specifically required for blood-brain barrier formation and function, probably by mediating lipid transport. Not required for central nervous system vascular morphogenesis. Acts as a transporter for tunicamycin, an inhibitor of asparagine-linked glycosylation. In placenta, acts as a receptor for ERVFRD-1/syncytin-2 and is required for trophoblast fusion.
• Tissue Specificity: In placenta, associated with trophoblast cells.
• Reactome Pathway: Synthesis of PC (R-HSA-1483191)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Microcephaly 15, primary, autosomal recessive	DISJTP2Q	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[3]
Amyloidosis	DISHTAI2	Strong	Biomarker	[4]
Colitis	DISAF7DD	Strong	Altered Expression	[5]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[6]
Gastric cancer	DISXGOUK	Strong	Biomarker	[2]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[7]
Hyperlipidemia	DIS61J3S	Strong	Biomarker	[8]
Intellectual disability	DISMBNXP	Strong	Biomarker	[1]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[9]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[9]
Lung neoplasm	DISVARNB	Strong	Genetic Variation	[9]
Microlissencephaly	DISUCKNT	Strong	Biomarker	[1]
Neu-Laxova syndrome 2	DISBF447	Strong	Genetic Variation	[10]
Stomach cancer	DISKIJSX	Strong	Biomarker	[2]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[5]
Zika virus infection	DISQUCTY	Strong	Biomarker	[11]
Fetal growth restriction	DIS5WEJ5	moderate	Altered Expression	[12]
Lung adenocarcinoma	DISD51WR	moderate	Altered Expression	[13]
Neoplasm	DISZKGEW	moderate	Biomarker	[2]
Obesity	DIS47Y1K	moderate	Biomarker	[14]
Autosomal recessive primary microcephaly	DIS29IE3	Supportive	Autosomal recessive	[1]
Isolated congenital microcephaly	DISUXHZ6	Limited	Biomarker	[15]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[16]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Lysophosphatidylcholine	DMOGFVH	Investigative	Sodium-dependent lysophosphatidylcholine symporter 1 (MFSD2A) increases the transport of Lysophosphatidylcholine.	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Sodium-dependent lysophosphatidylcholine symporter 1 (MFSD2A).	[17]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sodium-dependent lysophosphatidylcholine symporter 1 (MFSD2A).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sodium-dependent lysophosphatidylcholine symporter 1 (MFSD2A).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Sodium-dependent lysophosphatidylcholine symporter 1 (MFSD2A).	[20]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Sodium-dependent lysophosphatidylcholine symporter 1 (MFSD2A).	[18]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Sodium-dependent lysophosphatidylcholine symporter 1 (MFSD2A).	[21]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Sodium-dependent lysophosphatidylcholine symporter 1 (MFSD2A).	[22]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Sodium-dependent lysophosphatidylcholine symporter 1 (MFSD2A).	[24]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Sodium-dependent lysophosphatidylcholine symporter 1 (MFSD2A).	[25]
Melphalan	DMOLNHF	Approved	Melphalan increases the expression of Sodium-dependent lysophosphatidylcholine symporter 1 (MFSD2A).	[26]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Sodium-dependent lysophosphatidylcholine symporter 1 (MFSD2A).	[27]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Sodium-dependent lysophosphatidylcholine symporter 1 (MFSD2A).	[24]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Sodium-dependent lysophosphatidylcholine symporter 1 (MFSD2A).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Sodium-dependent lysophosphatidylcholine symporter 1 (MFSD2A).	[30]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Sodium-dependent lysophosphatidylcholine symporter 1 (MFSD2A).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Sodium-dependent lysophosphatidylcholine symporter 1 (MFSD2A).	[32]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Sodium-dependent lysophosphatidylcholine symporter 1 (MFSD2A).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Sodium-dependent lysophosphatidylcholine symporter 1 (MFSD2A).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Sodium-dependent lysophosphatidylcholine symporter 1 (MFSD2A).	[29]

References

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• [2] MFSD2A expression predicts better prognosis in gastric cancer.Biochem Biophys Res Commun. 2018 Nov 2;505(3):699-704. doi: 10.1016/j.bbrc.2018.09.156. Epub 2018 Oct 3.
• [3] Short-Term Fish Oil Treatment Changes the Composition of Phospholipids While Not Affecting the Expression of Mfsd2a Omega-3 Transporter in the Brain and Liver of the 5xFAD Mouse Model of Alzheimer's Disease.Nutrients. 2018 Sep 6;10(9):1250. doi: 10.3390/nu10091250.
• [4] Long-term consumption of alcohol exacerbates neural lesions by destroying the functional integrity of the blood-brain barrier.Drug Chem Toxicol. 2022 Jan;45(1):231-238. doi: 10.1080/01480545.2019.1681444. Epub 2019 Nov 20.
• [5] MFSD2A Promotes Endothelial Generation of Inflammation-Resolving Lipid Mediators and Reduces ColitisinMice.Gastroenterology. 2017 Nov;153(5):1363-1377.e6. doi: 10.1053/j.gastro.2017.07.048. Epub 2017 Aug 4.
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• [7] The prognostic value of major facilitator superfamily domain-containing protein 2A in patients with hepatocellular carcinoma.Aging (Albany NY). 2019 Oct 4;11(19):8474-8483. doi: 10.18632/aging.102333. Epub 2019 Oct 4.
• [8] Highfat treatment prevents postoperative cognitive dysfunction in a hyperlipidemia model by protecting the bloodbrain barrier via Mfsd2arelated signaling.Mol Med Rep. 2019 Nov;20(5):4226-4234. doi: 10.3892/mmr.2019.10675. Epub 2019 Sep 12.
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• [10] C-terminal region of apoptin affects chicken anemia virus replication and virulence.Virol J. 2017 Feb 21;14(1):38. doi: 10.1186/s12985-017-0713-9.
• [11] Zika virus degrades the -3 fatty acid transporter Mfsd2a in brain microvascular endothelial cells and impairs lipid homeostasis.Sci Adv. 2019 Oct 23;5(10):eaax7142. doi: 10.1126/sciadv.aax7142. eCollection 2019 Oct.
• [12] Impaired cell fusion and differentiation in placentae from patients with intrauterine growth restriction correlate with reduced levels of HERV envelope genes.J Mol Med (Berl). 2010 Nov;88(11):1143-56. doi: 10.1007/s00109-010-0656-8. Epub 2010 Jul 28.
• [13] MFSD2A is a novel lung tumor suppressor gene modulating cell cycle and matrix attachment.Mol Cancer. 2010 Mar 17;9:62. doi: 10.1186/1476-4598-9-62.
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• [15] The lysolipid transporter Mfsd2a regulates lipogenesis in the developing brain.PLoS Biol. 2018 Aug 3;16(8):e2006443. doi: 10.1371/journal.pbio.2006443. eCollection 2018 Aug.
• [16] Metastatic Brain Tumors Disrupt the Blood-Brain Barrier and Alter Lipid Metabolism by Inhibiting Expression of the Endothelial Cell Fatty Acid Transporter Mfsd2a.Sci Rep. 2018 May 29;8(1):8267. doi: 10.1038/s41598-018-26636-6.
• [17] In vitro assessment of drug-induced liver steatosis based on human dermal stem cell-derived hepatic cells. Arch Toxicol. 2016 Mar;90(3):677-89. doi: 10.1007/s00204-015-1483-z. Epub 2015 Feb 26.
• [18] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [19] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [22] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [23] 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.
• [24] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [25] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [26] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [27] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [28] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [29] 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.
• [30] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [31] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [32] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [33] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.