Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT77CX29)

• DOT Name: Sodium-dependent multivitamin transporter (SLC5A6)
• Synonyms: Na(+)-dependent multivitamin transporter; hSMVT; Solute carrier family 5 member 6
• Gene Name: SLC5A6
• Related Disease:
  Neurodegeneration, infantile-onset, biotin-responsive
  Inherited neurodegenerative disorder
• UniProt ID: SC5A6_HUMAN
• Pfam ID: PF00474
• Sequence:
  MSVGVSTSAPLSPTSGTSVGMSTFSIMDYVVFVLLLVLSLAIGLYHACRGWGRHTVGELL
  MADRKMGCLPVALSLLATFQSAVAILGVPSEIYRFGTQYWFLGCCYFLGLLIPAHIFIPV
  FYRLHLTSAYEYLELRFNKTVRVCGTVTFIFQMVIYMGVVLYAPSLALNAVTGFDLWLSV
  LALGIVCTVYTALGGLKAVIWTDVFQTLVMFLGQLAVIIVGSAKVGGLGRVWAVASQHGR
  ISGFELDPDPFVRHTFWTLAFGGVFMMLSLYGVNQAQVQRYLSSRTEKAAVLSCYAVFPF
  QQVSLCVGCLIGLVMFAYYQEYPMSIQQAQAAPDQFVLYFVMDLLKGLPGLPGLFIACLF
  SGSLSTISSAFNSLATVTMEDLIRPWFPEFSEARAIMLSRGLAFGYGLLCLGMAYISSQM
  GPVLQAAISIFGMVGGPLLGLFCLGMFFPCANPPGAVVGLLAGLVMAFWIGIGSIVTSMG
  SSMPPSPSNGSSFSLPTNLTVATVTTLMPLTTFSKPTGLQRFYSLSYLWYSAHNSTTVIV
  VGLIVSLLTGRMRGRSLNPATIYPVLPKLLSLLPLSCQKRLHCRSYGQDHLDTGLFPEKP
  RNGVLGDSRDKEAMALDGTAYQGSSSTCILQETSL
• Function: Sodium-dependent multivitamin transporter that mediates the electrogenic transport of pantothenate, biotin, lipoate and iodide. Functions as a Na(+)-coupled substrate symporter where the stoichiometry of Na(+):substrate is 2:1, creating an electrochemical Na(+) gradient used as driving force for substrate uptake. Required for biotin and pantothenate uptake in the intestine across the brush border membrane. Plays a role in the maintenance of intestinal mucosa integrity, by providing the gut mucosa with biotin. Contributes to the luminal uptake of biotin and pantothenate into the brain across the blood-brain barrier.
• Tissue Specificity: Expressed in microvessels of the brain (at protein level) . Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney, and pancreas .
• KEGG Pathway: Vitamin digestion and absorption (hsa04977)
• Reactome Pathway:
  Vitamin B5 (pantothenate) metabolism (R-HSA-199220)
  Transport of vitamins, nucleosides, and related molecules (R-HSA-425397)
  Biotin transport and metabolism (R-HSA-196780)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodegeneration, infantile-onset, biotin-responsive	DISTE7QO	Strong	Autosomal recessive	[1]
Inherited neurodegenerative disorder	DISPN7D2	Moderate	Autosomal recessive	[2]

This DOT Affected the Regulation of Drug Effects of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Pantothenic acid	DM091H2	Approved	Sodium-dependent multivitamin transporter (SLC5A6) increases the transport of Pantothenic acid.	[14]
THIOCTIC ACID	DMNFCXW	Investigative	Sodium-dependent multivitamin transporter (SLC5A6) increases the transport of THIOCTIC ACID.	[14]
Biotin	DMKMCE1	Investigative	Sodium-dependent multivitamin transporter (SLC5A6) increases the transport of Biotin.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Sodium-dependent multivitamin transporter (SLC5A6).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Sodium-dependent multivitamin transporter (SLC5A6).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sodium-dependent multivitamin transporter (SLC5A6).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sodium-dependent multivitamin transporter (SLC5A6).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Sodium-dependent multivitamin transporter (SLC5A6).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Sodium-dependent multivitamin transporter (SLC5A6).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Sodium-dependent multivitamin transporter (SLC5A6).	[8]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Sodium-dependent multivitamin transporter (SLC5A6).	[9]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate increases the expression of Sodium-dependent multivitamin transporter (SLC5A6).	[10]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Sodium-dependent multivitamin transporter (SLC5A6).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Sodium-dependent multivitamin transporter (SLC5A6).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Sodium-dependent multivitamin transporter (SLC5A6).	[13]

References

• [1] Mutations in SLC5A6 associated with brain, immune, bone, and intestinal dysfunction in a young child. Hum Genet. 2017 Feb;136(2):253-261. doi: 10.1007/s00439-016-1751-x. Epub 2016 Nov 30.
• [2] Identification and targeted management of a neurodegenerative disorder caused by biallelic mutations in SLC5A6. NPJ Genom Med. 2019 Nov 14;4:28. doi: 10.1038/s41525-019-0103-x. eCollection 2019.
• [3] 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.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [7] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [8] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [9] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [10] Di(2-ethylhexyl) phthalate induced thyroid toxicity via endoplasmic reticulum stress: In vivo and in vitro study. Environ Toxicol. 2022 Dec;37(12):2924-2936. doi: 10.1002/tox.23648. Epub 2022 Aug 25.
• [11] 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.
• [12] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [13] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [14] Human placental Na+-dependent multivitamin transporter. Cloning, functional expression, gene structure, and chromosomal localization. J Biol Chem. 1999 May 21;274(21):14875-83. doi: 10.1074/jbc.274.21.14875.
• [15] Biotin uptake by human proximal tubular epithelial cells: cellular and molecular aspects. Am J Physiol Renal Physiol. 2005 Apr;288(4):F823-31. doi: 10.1152/ajprenal.00375.2004. Epub 2004 Nov 23.