Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSCLZ04)

• DOT Name: Carnitine O-acetyltransferase (CRAT)
• Synonyms: Carnitine acetylase; EC 2.3.1.137; EC 2.3.1.7; Carnitine acetyltransferase; CAT; CrAT
• Gene Name: CRAT
• Related Disease: Neurodegeneration with brain iron accumulation 8
• UniProt ID: CACP_HUMAN
• PDB ID: 1NM8; 1S5O
• EC Number: 2.3.1.137; 2.3.1.7
• Pfam ID: PF00755
• Sequence:
  MLAFAARTVVKPLGFLKPFSLMKASSRFKAHQDALPRLPVPPLQQSLDHYLKALQPIVSE
  EEWAHTKQLVDEFQASGGVGERLQKGLERRARKTENWLSEWWLKTAYLQYRQPVVIYSSP
  GVMLPKQDFVDLQGQLRFAAKLIEGVLDFKVMIDNETLPVEYLGGKPLCMNQYYQILSSC
  RVPGPKQDTVSNFSKTKKPPTHITVVHNYQFFELDVYHSDGTPLTADQIFVQLEKIWNSS
  LQTNKEPVGILTSNHRNSWAKAYNTLIKDKVNRDSVRSIQKSIFTVCLDATMPRVSEDVY
  RSHVAGQMLHGGGSRLNSGNRWFDKTLQFIVAEDGSCGLVYEHAAAEGPPIVTLLDYVIE
  YTKKPELVRSPLVPLPMPKKLRFNITPEIKSDIEKAKQNLSIMIQDLDITVMVFHHFGKD
  FPKSEKLSPDAFIQMALQLAYYRIYGQACATYESASLRMFHLGRTDTIRSASMDSLTFVK
  AMDDSSVTEHQKVELLRKAVQAHRGYTDRAIRGEAFDRHLLGLKLQAIEDLVSMPDIFMD
  TSYAIAMHFHLSTSQVPAKTDCVMFFGPVVPDGYGVCYNPMEAHINFSLSAYNSCAETNA
  ARLAHYLEKALLDMRALLQSHPRAKL
• Function: Catalyzes the reversible transfer of acyl groups from carnitine to coenzyme A (CoA) and regulates the acyl-CoA/CoA ratio. Also plays a crucial role in the transport of fatty acids for beta-oxidation. Responsible for the synthesis of short- and branched-chain acylcarnitines. Active towards some branched-chain amino acid oxidation pathway (BCAAO) intermediates. Trans-2-enoyl-CoAs and 2-methylacyl-CoAs are poor substrates.
• Tissue Specificity: Mostly in skeletal muscle, less in heart, liver and pancreas, only weakly detectable in brain, placenta, lung and kidney.
• Reactome Pathway:
  Peroxisomal protein import (R-HSA-9033241)
  Beta-oxidation of pristanoyl-CoA (R-HSA-389887)
• BioCyc Pathway: MetaCyc:HS01816-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodegeneration with brain iron accumulation 8	DIS157F6	Limited	Autosomal recessive	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Clofibrate	DMPC1J7	Approved	Carnitine O-acetyltransferase (CRAT) increases the Hyperplasia ADR of Clofibrate.	[12]

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 Carnitine O-acetyltransferase (CRAT).	[2]

9 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 Carnitine O-acetyltransferase (CRAT).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Carnitine O-acetyltransferase (CRAT).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Carnitine O-acetyltransferase (CRAT).	[5]
Selenium	DM25CGV	Approved	Selenium increases the expression of Carnitine O-acetyltransferase (CRAT).	[6]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Carnitine O-acetyltransferase (CRAT).	[7]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Carnitine O-acetyltransferase (CRAT).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Carnitine O-acetyltransferase (CRAT).	[9]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Carnitine O-acetyltransferase (CRAT).	[10]
Benzoquinone	DMNBA0G	Investigative	Benzoquinone decreases the expression of Carnitine O-acetyltransferase (CRAT).	[11]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [9] 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.
• [10] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [11] l-Carnitine protects against 1,4-benzoquinone-induced apoptosis and DNA damage by suppressing oxidative stress and promoting fatty acid oxidation in K562 cells. Environ Toxicol. 2020 Oct;35(10):1033-1042. doi: 10.1002/tox.22939. Epub 2020 Jun 1.
• [12] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.