Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWK68MM)

• DOT Name: Peroxisomal carnitine O-octanoyltransferase (CROT)
• Synonyms: COT; EC 2.3.1.137
• Gene Name: CROT
• Related Disease:
  Anaplastic large cell lymphoma
  Non-alcoholic fatty liver disease
  High blood pressure
  Lung carcinoma
  Stroke
  Thyroid gland papillary carcinoma
• UniProt ID: OCTC_HUMAN
• EC Number: 2.3.1.137
• Pfam ID: PF00755
• Sequence:
  MENQLAKSTEERTFQYQDSLPSLPVPSLEESLKKYLESVKPFANQEEYKKTEEIVQKFQS
  GIGEKLHQKLLERAKGKRNWLEEWWLNVAYLDVRIPSQLNVNFAGPAAHFEHYWPPKEGT
  QLERGSITLWHNLNYWQLLRKEKVPVHKVGNTPLDMNQFRMLFSTCKVPGITRDSIMNYF
  RTESEGRSPNHIVVLCRGRAFVFDVIHEGCLVTPPELLRQLTYIHKKCHSEPDGPGIAAL
  TSEERTRWAKAREYLIGLDPENLALLEKIQSSLLVYSMEDSSPHVTPEDYSEIIAAILIG
  DPTVRWGDKSYNLISFSNGVFGCNCDHAPFDAMIMVNISYYVDEKIFQNEGRWKGSEKVR
  DIPLPEELIFIVDEKVLNDINQAKAQYLREASDLQIAAYAFTSFGKKLTKNKMLHPDTFI
  QLALQLAYYRLHGHPGCCYETAMTRHFYHGRTETMRSCTVEAVRWCQSMQDPSVNLRERQ
  QKMLQAFAKHNKMMKDCSAGKGFDRHLLGLLLIAKEEGLPVPELFTDPLFSKSGGGGNFV
  LSTSLVGYLRVQGVVVPMVHNGYGFFYHIRDDRFVVACSAWKSCPETDAEKLVQLTFCAF
  HDMIQLMNSTHL
• Function: Beta-oxidation of fatty acids. The highest activity concerns the C6 to C10 chain length substrate. Converts the end product of pristanic acid beta oxidation, 4,8-dimethylnonanoyl-CoA, to its corresponding carnitine ester.
• KEGG Pathway: Peroxisome (hsa04146)
• Reactome Pathway:
  Peroxisomal protein import (R-HSA-9033241)
  Beta-oxidation of pristanoyl-CoA (R-HSA-389887)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anaplastic large cell lymphoma	DISP4D1R	Strong	Biomarker	[1]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[2]
High blood pressure	DISY2OHH	Limited	Biomarker	[3]
Lung carcinoma	DISTR26C	Limited	Genetic Variation	[4]
Stroke	DISX6UHX	Limited	Biomarker	[3]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Altered Expression	[5]

4 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 Peroxisomal carnitine O-octanoyltransferase (CROT).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Peroxisomal carnitine O-octanoyltransferase (CROT).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Peroxisomal carnitine O-octanoyltransferase (CROT).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Peroxisomal carnitine O-octanoyltransferase (CROT).	[19]

15 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 Peroxisomal carnitine O-octanoyltransferase (CROT).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Peroxisomal carnitine O-octanoyltransferase (CROT).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Peroxisomal carnitine O-octanoyltransferase (CROT).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Peroxisomal carnitine O-octanoyltransferase (CROT).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat affects the expression of Peroxisomal carnitine O-octanoyltransferase (CROT).	[12]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Peroxisomal carnitine O-octanoyltransferase (CROT).	[13]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Peroxisomal carnitine O-octanoyltransferase (CROT).	[14]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Peroxisomal carnitine O-octanoyltransferase (CROT).	[15]
Deoxycholic acid	DM3GYAL	Approved	Deoxycholic acid decreases the expression of Peroxisomal carnitine O-octanoyltransferase (CROT).	[16]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Peroxisomal carnitine O-octanoyltransferase (CROT).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Peroxisomal carnitine O-octanoyltransferase (CROT).	[12]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone decreases the expression of Peroxisomal carnitine O-octanoyltransferase (CROT).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Peroxisomal carnitine O-octanoyltransferase (CROT).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Peroxisomal carnitine O-octanoyltransferase (CROT).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Peroxisomal carnitine O-octanoyltransferase (CROT).	[22]

References

• [1] Involvement of Cot activity in the proliferation of ALCL lymphoma cells.Biochem Biophys Res Commun. 2011 Aug 12;411(4):655-60. doi: 10.1016/j.bbrc.2011.06.157. Epub 2011 Jun 29.
• [2] Hepatic miR-33a/miR-144 and their target gene ABCA1 are associated with steatohepatitis in morbidly obese subjects. Liver Int. 2016 Sep;36(9):1383-91.
• [3] miR?26a?pDbp and miR?1aCrot/Mrpl4 interaction pairs crucial for the development of hypertension and stroke.Mol Med Rep. 2019 Nov;20(5):4151-4167. doi: 10.3892/mmr.2019.10679. Epub 2019 Sep 12.
• [4] Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.Nat Genet. 2017 Jul;49(7):1126-1132. doi: 10.1038/ng.3892. Epub 2017 Jun 12.
• [5] Aberrant expression of COT is related to recurrence of papillary thyroid cancer.Medicine (Baltimore). 2015 Feb;94(6):e548. doi: 10.1097/MD.0000000000000548.
• [6] 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.
• [7] 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.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [10] 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.
• [11] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [12] 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.
• [13] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [14] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [15] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [16] Advantageous use of HepaRG cells for the screening and mechanistic study of drug-induced steatosis. Toxicol Appl Pharmacol. 2016 Jul 1;302:1-9. doi: 10.1016/j.taap.2016.04.007. Epub 2016 Apr 16.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.