Details of Drug Off-Target (DOT)

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

• DOT Name: Citrate synthase, mitochondrial (CS)
• Synonyms: EC 2.3.3.1; Citrate (Si)-synthase
• Gene Name: CS
• UniProt ID: CISY_HUMAN
• PDB ID: 5UZP; 5UZQ; 5UZR
• EC Number: 2.3.3.1
• Pfam ID: PF00285
• Sequence:
  MALLTAAARLLGTKNASCLVLAARHASASSTNLKDILADLIPKEQARIKTFRQQHGKTVV
  GQITVDMMYGGMRGMKGLVYETSVLDPDEGIRFRGFSIPECQKLLPKAKGGEEPLPEGLF
  WLLVTGHIPTEEQVSWLSKEWAKRAALPSHVVTMLDNFPTNLHPMSQLSAAVTALNSESN
  FARAYAQGISRTKYWELIYEDSMDLIAKLPCVAAKIYRNLYREGSGIGAIDSNLDWSHNF
  TNMLGYTDHQFTELTRLYLTIHSDHEGGNVSAHTSHLVGSALSDPYLSFAAAMNGLAGPL
  HGLANQEVLVWLTQLQKEVGKDVSDEKLRDYIWNTLNSGRVVPGYGHAVLRKTDPRYTCQ
  REFALKHLPNDPMFKLVAQLYKIVPNVLLEQGKAKNPWPNVDAHSGVLLQYYGMTEMNYY
  TVLFGVSRALGVLAQLIWSRALGFPLERPKSMSTEGLMKFVDSKSG
• KEGG Pathway:
  Citrate cycle (TCA cycle) (hsa00020)
  Glyoxylate and dicarboxylate metabolism (hsa00630)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  2-Oxocarboxylic acid metabolism (hsa01210)
  Biosynthesis of amino acids (hsa01230)
• Reactome Pathway:
  Citric acid cycle (TCA cycle) (R-HSA-71403)
  Mitochondrial protein import (R-HSA-1268020)
• BioCyc Pathway: MetaCyc:ENSG00000062485-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Josamycin	DMKJ8LB	Approved	Citrate synthase, mitochondrial (CS) affects the response to substance of Josamycin.	[16]

14 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 Citrate synthase, mitochondrial (CS).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Citrate synthase, mitochondrial (CS).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Citrate synthase, mitochondrial (CS).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Citrate synthase, mitochondrial (CS).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Citrate synthase, mitochondrial (CS).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Citrate synthase, mitochondrial (CS).	[6]
Triclosan	DMZUR4N	Approved	Triclosan affects the expression of Citrate synthase, mitochondrial (CS).	[7]
Marinol	DM70IK5	Approved	Marinol increases the expression of Citrate synthase, mitochondrial (CS).	[8]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Citrate synthase, mitochondrial (CS).	[9]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Citrate synthase, mitochondrial (CS).	[10]
Dopamine	DMPGUCF	Approved	Dopamine increases the expression of Citrate synthase, mitochondrial (CS).	[11]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the activity of Citrate synthase, mitochondrial (CS).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Citrate synthase, mitochondrial (CS).	[14]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Citrate synthase, mitochondrial (CS).	[15]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Citrate synthase, mitochondrial (CS).	[13]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [4] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [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] Nucleophosmin in the pathogenesis of arsenic-related bladder carcinogenesis revealed by quantitative proteomics. Toxicol Appl Pharmacol. 2010 Jan 15;242(2):126-35. doi: 10.1016/j.taap.2009.09.016. Epub 2009 Oct 7.
• [7] The modulatory effect of triclosan on the reversion of the activated phenotype of LX-2 hepatic stellate cells. J Biochem Mol Toxicol. 2020 Jan;34(1):e22413. doi: 10.1002/jbt.22413. Epub 2019 Nov 12.
• [8] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [9] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [10] Zidovudine myopathy: a distinctive disorder associated with mitochondrial dysfunction. Ann Neurol. 1991 Jun;29(6):606-14. doi: 10.1002/ana.410290607.
• [11] Mitochondrial proteomics investigation of a cellular model of impaired dopamine homeostasis, an early step in Parkinson's disease pathogenesis. Mol Biosyst. 2014 Jun;10(6):1332-44.
• [12] Resveratrol inhibits proliferation, angiogenesis and induces apoptosis in colon cancer cells: calorie restriction is the force to the cytotoxicity. Hum Exp Toxicol. 2013 Oct;32(10):1067-80. doi: 10.1177/0960327113475679. Epub 2013 Mar 27.
• [13] 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.
• [14] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [15] Lipid Rafts Disruption Increases Ochratoxin A Cytotoxicity to Hepatocytes. J Biochem Mol Toxicol. 2016 Feb;30(2):71-9. doi: 10.1002/jbt.21738. Epub 2015 Aug 25.
• [16] A genome-wide analysis of targets of macrolide antibiotics in mammalian cells. J Biol Chem. 2020 Feb 14;295(7):2057-2067. doi: 10.1074/jbc.RA119.010770. Epub 2020 Jan 8.