Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAQ6YWB)

• DOT Name: Nucleotide sugar transporter SLC35D1 (SLC35D1)
• Synonyms: Solute carrier family 35 member D1; UDP-galactose transporter-related protein 7; UGTrel7; UDP-glucuronic acid/UDP-N-acetylgalactosamine transporter; UDP-GlcA/UDP-GalNAc transporter
• Gene Name: SLC35D1
• Related Disease: Schneckenbecken dysplasia
• UniProt ID: S35D1_HUMAN
• Pfam ID: PF03151
• Sequence:
  MAEVHRRQHARVKGEAPAKSSTLRDEEELGMASAETLTVFLKLLAAGFYGVSSFLIVVVN
  KSVLTNYRFPSSLCVGLGQMVATVAVLWVGKALRVVKFPDLDRNVPRKTFPLPLLYFGNQ
  ITGLFSTKKLNLPMFTVLRRFSILFTMFAEGVLLKKTFSWGIKMTVFAMIIGAFVAASSD
  LAFDLEGYAFILINDVLTAANGAYVKQKLDSKELGKYGLLYYNALFMILPTLAIAYFTGD
  AQKAVEFEGWADTLFLLQFTLSCVMGFILMYATVLCTQYNSALTTTIVGCIKNILITYIG
  MVFGGDYIFTWTNFIGLNISIAGSLVYSYITFTEEQLSKQSEANNKLDIKGKGAV
• Function: Antiporter that transports nucleotide sugars across the endoplasmic reticulum (ER) membrane in exchange for either their cognate nucleoside monophosphate or another nucleotide sugar. Transports various UDP-sugars including UDP-N-acetyl-alpha-D-glucosamine (UDP-GlcNAc), UDP-N-acetyl-alpha-D-galactosamine (UDP-GalNAc) and UDP-alpha-D-glucuronate (UDP-GlcA), which are used by ER glucosyltransferases as sugar donors for the synthesis of sugar chains of glycoproteins, glycolipids and oligosaccharides. May couple UDP-GlcNAc or UDP-GalNAc efflux to UDP-GlcA influx into the ER lumen that in turn stimulates glucuronidation and subsequent excretion of endobiotics and xenobiotics. Plays a role in chondroitin sulfate biosynthesis, which is important for formation of cartilage extracellular matrix and normal skeletal development.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway:
  Defective SLC35D1 causes SCHBCKD (R-HSA-5579020)
  Transport of nucleotide sugars (R-HSA-727802)
  Formation of the active cofactor, UDP-glucuronate (R-HSA-173599)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Schneckenbecken dysplasia	DIS2NNB4	Definitive	Autosomal recessive	[1]

2 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 Nucleotide sugar transporter SLC35D1 (SLC35D1).	[2]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Nucleotide sugar transporter SLC35D1 (SLC35D1).	[15]

17 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 Nucleotide sugar transporter SLC35D1 (SLC35D1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Nucleotide sugar transporter SLC35D1 (SLC35D1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Nucleotide sugar transporter SLC35D1 (SLC35D1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Nucleotide sugar transporter SLC35D1 (SLC35D1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Nucleotide sugar transporter SLC35D1 (SLC35D1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Nucleotide sugar transporter SLC35D1 (SLC35D1).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Nucleotide sugar transporter SLC35D1 (SLC35D1).	[9]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Nucleotide sugar transporter SLC35D1 (SLC35D1).	[10]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Nucleotide sugar transporter SLC35D1 (SLC35D1).	[11]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Nucleotide sugar transporter SLC35D1 (SLC35D1).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Nucleotide sugar transporter SLC35D1 (SLC35D1).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Nucleotide sugar transporter SLC35D1 (SLC35D1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Nucleotide sugar transporter SLC35D1 (SLC35D1).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Nucleotide sugar transporter SLC35D1 (SLC35D1).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Nucleotide sugar transporter SLC35D1 (SLC35D1).	[17]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Nucleotide sugar transporter SLC35D1 (SLC35D1).	[8]
Hydroxydimethylarsine Oxide	DMPS2B1	Investigative	Hydroxydimethylarsine Oxide increases the expression of Nucleotide sugar transporter SLC35D1 (SLC35D1).	[18]

References

• [1] Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human. Nat Med. 2007 Nov;13(11):1363-7. doi: 10.1038/nm1655. Epub 2007 Oct 21.
• [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] 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.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] 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.
• [11] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [12] Differential gene expression in human hepatocyte cell lines exposed to the antiretroviral agent zidovudine. Arch Toxicol. 2014 Mar;88(3):609-23. doi: 10.1007/s00204-013-1169-3. Epub 2013 Nov 30.
• [13] 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.
• [14] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [15] 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.
• [16] 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.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] Identification of interspecies concordance of mechanisms of arsenic-induced bladder cancer. Toxicol In Vitro. 2007 Dec;21(8):1513-29. doi: 10.1016/j.tiv.2007.06.021. Epub 2007 Jul 21.