Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMMNQ2E)

• DOT Name: Solute carrier family 4 member 11 (SLC4A11)
• Synonyms: Sodium borate cotransporter 1; NaBC1
• Gene Name: SLC4A11
• Related Disease:
  Congenital hereditary endothelial dystrophy of cornea
  Corneal dystrophy, Fuchs endothelial, 4
  Corneal dystrophy-perceptive deafness syndrome
  Fuchs' endothelial dystrophy
• UniProt ID: S4A11_HUMAN
• PDB ID: 7X1G; 7X1H; 7X1I; 7X1J
• Pfam ID: PF00955
• Sequence:
  MAAATRRVFHLQPCENSPTMSQNGYFEDSSYYKCDTDDTFEAREEILGDEAFDTANSSIV
  SGESIRFFVNVNLEMQATNTENEATSGGCVLLHTSRKYLKLKNFKEEIRAHRDLDGFLAQ
  ASIVLNETATSLDNVLRTMLRRFARDPDNNEPNCNLDLLMAMLFTDAGAPMRGKVHLLSD
  TIQGVTATVTGVRYQQSWLCIICTMKALQKRHVCISRLVRPQNWGENSCEVRFVILVLAP
  PKMKSTKTAMEVARTFATMFSDIAFRQKLLETRTEEEFKEALVHQRQLLTMVSHGPVAPR
  TKERSTVSLPAHRHPEPPKCKDFVPFGKGIREDIARRFPLYPLDFTDGIIGKNKAVGKYI
  TTTLFLYFACLLPTIAFGSLNDENTDGAIDVQKTIAGQSIGGLLYALFSGQPLVILLTTA
  PLALYIQVIRVICDDYDLDFNSFYAWTGLWNSFFLALYAFFNLSLVMSLFKRSTEEIIAL
  FISITFVLDAVKGTVKIFWKYYYGHYLDDYHTKRTSSLVSLSGLGASLNASLHTALNASF
  LASPTELPSATHSGQATAVLSLLIMLGTLWLGYTLYQFKKSPYLHPCVREILSDCALPIA
  VLAFSLISSHGFREIEMSKFRYNPSESPFAMAQIQSLSLRAVSGAMGLGFLLSMLFFIEQ
  NLVAALVNAPENRLVKGTAYHWDLLLLAIINTGLSLFGLPWIHAAYPHSPLHVRALALVE
  ERVENGHIYDTIVNVKETRLTSLGASVLVGLSLLLLPVPLQWIPKPVLYGLFLYIALTSL
  DGNQLVQRVALLLKEQTAYPPTHYIRRVPQRKIHYFTGLQVLQLLLLCAFGMSSLPYMKM
  IFPLIMIAMIPIRYILLPRIIEAKYLDVMDAEHRP
• Function: Multifunctional transporter with an impact in cell morphology and differentiation. In the presence of borate B(OH)4(-), acts as a voltage-dependent electrogenic Na(+)-coupled B(OH)4(-) cotransporter controlling boron homeostasis. At early stages of stem cell differentiation, participates in synergy with ITGA5-ITGB1 and ITGAV-ITGB3 integrins and BMPR1A to promote cell adhesion and contractility that drives differentiation toward osteogenic commitment while inhibiting adipogenesis. In the absence of B(OH)4(-), acts as a Na(+)-coupled OH(-) or H(+) permeable channel with implications in cellular redox balance. Regulates the oxidative stress response in corneal endothelium by enhancing antioxidant defenses and protecting cells from reactive oxygen species. In response to hypo-osmotic challenge, also acts as a water permeable channel at the basolateral cell membrane of corneal endothelial cells and facilitates transendothelial fluid reabsorption in the aqueous humor. In the presence of ammonia, acts as an electrogenic NH3/H(+) cotransporter and may play a role in ammonia transport and reabsorption in renal Henle's loop epithelium.
• Tissue Specificity: Widely expressed. Highly expressed in kidney, testis, salivary gland, thyroid, trachea and corneal endothelium. Not detected in retina and lymphocytes.; [Isoform 3]: Expressed in corneal endothelium (at protein level).; [Isoform 5]: The predominant isoform in corneal endothelium (at protein level).

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 hereditary endothelial dystrophy of cornea	DISHLPKQ	Strong	Autosomal recessive	[1]
Corneal dystrophy, Fuchs endothelial, 4	DISHIF57	Strong	Autosomal dominant	[2]
Corneal dystrophy-perceptive deafness syndrome	DISMRYNA	Strong	Autosomal recessive	[3]
Fuchs' endothelial dystrophy	DISL7TXC	Supportive	Autosomal dominant	[4]

1 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 Solute carrier family 4 member 11 (SLC4A11).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Solute carrier family 4 member 11 (SLC4A11).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Solute carrier family 4 member 11 (SLC4A11).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Solute carrier family 4 member 11 (SLC4A11).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Solute carrier family 4 member 11 (SLC4A11).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Solute carrier family 4 member 11 (SLC4A11).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Solute carrier family 4 member 11 (SLC4A11).	[9]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Solute carrier family 4 member 11 (SLC4A11).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Solute carrier family 4 member 11 (SLC4A11).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Solute carrier family 4 member 11 (SLC4A11).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Solute carrier family 4 member 11 (SLC4A11).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Solute carrier family 4 member 11 (SLC4A11).	[15]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Fuchs Endothelial Corneal Dystrophy in a Heterozygous Carrier of Congenital Hereditary Endothelial Dystrophy Type 2 with a Novel Mutation in SLC4A11. Ophthalmic Genet. 2015;36(3):284-6. doi: 10.3109/13816810.2014.881510.
• [3] Borate transporter SLC4A11 mutations cause both Harboyan syndrome and non-syndromic corneal endothelial dystrophy. J Med Genet. 2007 May;44(5):322-6. doi: 10.1136/jmg.2006.046904. Epub 2007 Jan 12.
• [4] Missense mutations in the sodium borate cotransporter SLC4A11 cause late-onset Fuchs corneal dystrophy. Hum Mutat. 2010 Nov;31(11):1261-8. doi: 10.1002/humu.21356. Epub 2010 Oct 14.
• [5] 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.
• [6] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [11] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [12] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [13] 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.
• [14] Low dose of bisphenol a modulates ovarian cancer gene expression profile and promotes epithelial to mesenchymal transition via canonical Wnt pathway. Toxicol Sci. 2018 Aug 1;164(2):527-538.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.