Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ01UJZ)

• DOT Name: Acetyl-coenzyme A transporter 1 (SLC33A1)
• Synonyms: AT-1; Acetyl-CoA transporter 1; Solute carrier family 33 member 1
• Gene Name: SLC33A1
• Related Disease:
  Huppke-Brendel syndrome
  Hereditary spastic paraplegia 42
• UniProt ID: ACATN_HUMAN
• Pfam ID: PF13000
• Sequence:
  MSPTISHKDSSRQRRPGNFSHSLDMKSGPLPPGGWDDSHLDSAGREGDREALLGDTGTGD
  FLKAPQSFRAELSSILLLLFLYVLQGIPLGLAGSIPLILQSKNVSYTDQAFFSFVFWPFS
  LKLLWAPLVDAVYVKNFGRRKSWLVPTQYILGLFMIYLSTQVDRLLGNTDDRTPDVIALT
  VAFFLFEFLAATQDIAVDGWALTMLSRENVGYASTCNSVGQTAGYFLGNVLFLALESADF
  CNKYLRFQPQPRGIVTLSDFLFFWGTVFLITTTLVALLKKENEVSVVKEETQGITDTYKL
  LFAIIKMPAVLTFCLLILTAKIGFSAADAVTGLKLVEEGVPKEHLALLAVPMVPLQIILP
  LIISKYTAGPQPLNTFYKAMPYRLLLGLEYALLVWWTPKVEHQGGFPIYYYIVVLLSYAL
  HQVTVYSMYVSIMAFNAKVSDPLIGGTYMTLLNTVSNLGGNWPSTVALWLVDPLTVKECV
  GASNQNCRTPDAVELCKKLGGSCVTALDGYYVESIICVFIGFGWWFFLGPKFKKLQDEGS
  SSWKCKRNN
• Function: Acetyl-CoA transporter that mediates active acetyl-CoA import through the endoplasmic reticulum (ER) membrane into the ER lumen where specific ER-based acetyl-CoA:lysine acetyltransferases are responsible for the acetylation of ER-based protein substrates, such as BACE1. Necessary for O-acetylation of gangliosides.
• Tissue Specificity: Ubiquitous. Detected in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. With strongest signals in pancreas.
• KEGG Pathway:
  Glycosphingolipid biosynthesis - ganglio series (hsa00604)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Defective SLC33A1 causes spastic paraplegia 42 (SPG42) (R-HSA-5619061)
  Transport of vitamins, nucleosides, and related molecules (R-HSA-425397)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Huppke-Brendel syndrome	DISPXQ3Q	Definitive	Autosomal recessive	[1]
Hereditary spastic paraplegia 42	DIS4AJAI	Supportive	Autosomal dominant	[2]

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 Acetyl-coenzyme A transporter 1 (SLC33A1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Acetyl-coenzyme A transporter 1 (SLC33A1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Acetyl-coenzyme A transporter 1 (SLC33A1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Acetyl-coenzyme A transporter 1 (SLC33A1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Acetyl-coenzyme A transporter 1 (SLC33A1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Acetyl-coenzyme A transporter 1 (SLC33A1).	[8]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Acetyl-coenzyme A transporter 1 (SLC33A1).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Acetyl-coenzyme A transporter 1 (SLC33A1).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Acetyl-coenzyme A transporter 1 (SLC33A1).	[11]

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] A missense mutation in SLC33A1, which encodes the acetyl-CoA transporter, causes autosomal-dominant spastic paraplegia (SPG42). Am J Hum Genet. 2008 Dec;83(6):752-9. doi: 10.1016/j.ajhg.2008.11.003.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [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] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [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] 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.
• [10] 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.
• [11] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.