Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG92DK5)

• DOT Name: UDP-N-acetylglucosamine transporter (SLC35A3)
• Synonyms: Golgi UDP-GlcNAc transporter; Solute carrier family 35 member A3
• Gene Name: SLC35A3
• Related Disease: Autism spectrum disorder - epilepsy - arthrogryposis syndrome
• UniProt ID: S35A3_HUMAN
• Pfam ID: PF04142
• Sequence:
  MFANLKYVSLGILVFQTTSLVLTMRYSRTLKEEGPRYLSSTAVVVAELLKIMACILLVYK
  DSKCSLRALNRVLHDEILNKPMETLKLAIPSGIYTLQNNLLYVALSNLDAATYQVTYQLK
  ILTTALFSVSMLSKKLGVYQWLSLVILMTGVAFVQWPSDSQLDSKELSAGSQFVGLMAVL
  TACFSSGFAGVYFEKILKETKQSVWIRNIQLGFFGSIFGLMGVYIYDGELVSKNGFFQGY
  NRLTWIVVVLQALGGLVIAAVIKYADNILKGFATSLSIILSTLISYFWLQDFVPTSVFFL
  GAILVITATFLYGYDPKPAGNPTKA
• Function: Transports diphosphate-N-acetylglucosamine (UDP-GlcNAc) from the cytosol into the lumen of the Golgi apparatus, functioning as an antiporter that exchanges UDP-N-acetyl-alpha-D-glucosamine for UMP. May supply UDP-GlcNAc as substrate for Golgi-resident glycosyltransferases that generate highly branched, multiantennary complex N-glycans and keratan sulfate. However, the exact role of SLC35A3 still needs to be elucidated, it could be a member of a catalytically more efficient multiprotein complex rather than function independently as a single transporter.
• Reactome Pathway:
  Transport of nucleotide sugars (R-HSA-727802)
  Defective SLC35A3 causes arthrogryposis, mental retardation, and seizures (AMRS) (R-HSA-5619083)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism spectrum disorder - epilepsy - arthrogryposis syndrome	DISZ6MFS	Strong	Autosomal recessive	[1]

9 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 UDP-N-acetylglucosamine transporter (SLC35A3).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of UDP-N-acetylglucosamine transporter (SLC35A3).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of UDP-N-acetylglucosamine transporter (SLC35A3).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of UDP-N-acetylglucosamine transporter (SLC35A3).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of UDP-N-acetylglucosamine transporter (SLC35A3).	[6]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of UDP-N-acetylglucosamine transporter (SLC35A3).	[8]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of UDP-N-acetylglucosamine transporter (SLC35A3).	[10]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of UDP-N-acetylglucosamine transporter (SLC35A3).	[11]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of UDP-N-acetylglucosamine transporter (SLC35A3).	[12]

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 UDP-N-acetylglucosamine transporter (SLC35A3).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of UDP-N-acetylglucosamine transporter (SLC35A3).	[9]

References

• [1] A missense mutation in the bovine SLC35A3 gene, encoding a UDP-N-acetylglucosamine transporter, causes complex vertebral malformation. Genome Res. 2006 Jan;16(1):97-105. doi: 10.1101/gr.3690506. Epub 2005 Dec 12.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] 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.
• [8] Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One. 2007 Nov 14;2(11):e1187. doi: 10.1371/journal.pone.0001187.
• [9] 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.
• [10] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [11] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [12] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.