Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF2UVNV)

• DOT Name: Aconitate hydratase, mitochondrial (ACO2)
• Synonyms: Aconitase; EC 4.2.1.3; Citrate hydro-lyase
• Gene Name: ACO2
• Related Disease:
  Infantile cerebellar-retinal degeneration
  Optic atrophy 9
  Obsolete autosomal recessive optic atrophy
• UniProt ID: ACON_HUMAN
• EC Number: 4.2.1.3
• Pfam ID: PF00330 ; PF00694
• Sequence:
  MAPYSLLVTRLQKALGVRQYHVASVLCQRAKVAMSHFEPNEYIHYDLLEKNINIVRKRLN
  RPLTLSEKIVYGHLDDPASQEIERGKSYLRLRPDRVAMQDATAQMAMLQFISSGLSKVAV
  PSTIHCDHLIEAQVGGEKDLRRAKDINQEVYNFLATAGAKYGVGFWKPGSGIIHQIILEN
  YAYPGVLLIGTDSHTPNGGGLGGICIGVGGADAVDVMAGIPWELKCPKVIGVKLTGSLSG
  WSSPKDVILKVAGILTVKGGTGAIVEYHGPGVDSISCTGMATICNMGAEIGATTSVFPYN
  HRMKKYLSKTGREDIANLADEFKDHLVPDPGCHYDQLIEINLSELKPHINGPFTPDLAHP
  VAEVGKVAEKEGWPLDIRVGLIGSCTNSSYEDMGRSAAVAKQALAHGLKCKSQFTITPGS
  EQIRATIERDGYAQILRDLGGIVLANACGPCIGQWDRKDIKKGEKNTIVTSYNRNFTGRN
  DANPETHAFVTSPEIVTALAIAGTLKFNPETDYLTGTDGKKFRLEAPDADELPKGEFDPG
  QDTYQHPPKDSSGQHVDVSPTSQRLQLLEPFDKWDGKDLEDLQILIKVKGKCTTDHISAA
  GPWLKFRGHLDNISNNLLIGAINIENGKANSVRNAVTQEFGPVPDTARYYKKHGIRWVVI
  GDENYGEGSSREHAALEPRHLGGRAIITKSFARIHETNLKKQGLLPLTFADPADYNKIHP
  VDKLTIQGLKDFTPGKPLKCIIKHPNGTQETILLNHTFNETQIEWFRAGSALNRMKELQQ
• Function: Catalyzes the isomerization of citrate to isocitrate via cis-aconitate.
• 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:HS02077-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Infantile cerebellar-retinal degeneration	DISAX8L9	Strong	Autosomal recessive	[1]
Optic atrophy 9	DISNV6ZG	Strong	Autosomal recessive	[2]
Obsolete autosomal recessive optic atrophy	DISP0XVX	Supportive	Autosomal recessive	[3]

17 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 Aconitate hydratase, mitochondrial (ACO2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Aconitate hydratase, mitochondrial (ACO2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Aconitate hydratase, mitochondrial (ACO2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the activity of Aconitate hydratase, mitochondrial (ACO2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Aconitate hydratase, mitochondrial (ACO2).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Aconitate hydratase, mitochondrial (ACO2).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Aconitate hydratase, mitochondrial (ACO2).	[10]
Selenium	DM25CGV	Approved	Selenium increases the expression of Aconitate hydratase, mitochondrial (ACO2).	[11]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Aconitate hydratase, mitochondrial (ACO2).	[12]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Aconitate hydratase, mitochondrial (ACO2).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Aconitate hydratase, mitochondrial (ACO2).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Aconitate hydratase, mitochondrial (ACO2).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Aconitate hydratase, mitochondrial (ACO2).	[15]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the activity of Aconitate hydratase, mitochondrial (ACO2).	[17]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the activity of Aconitate hydratase, mitochondrial (ACO2).	[18]
Manganese	DMKT129	Investigative	Manganese decreases the expression of Aconitate hydratase, mitochondrial (ACO2).	[19]
Linalool	DMGZQ5P	Investigative	Linalool increases the expression of Aconitate hydratase, mitochondrial (ACO2).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Aconitate hydratase, mitochondrial (ACO2).	[16]

References

• [1] Infantile cerebellar-retinal degeneration associated with a mutation in mitochondrial aconitase, ACO2. Am J Hum Genet. 2012 Mar 9;90(3):518-23. doi: 10.1016/j.ajhg.2012.01.009.
• [2] Increased Survival and Partly Preserved Cognition in a Patient With ACO2-Related Disease Secondary to a Novel Variant. J Child Neurol. 2017 Aug;32(9):840-845. doi: 10.1177/0883073817711527. Epub 2017 May 25.
• [3] Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy. J Med Genet. 2014 Dec;51(12):834-8. doi: 10.1136/jmedgenet-2014-102532. Epub 2014 Oct 28.
• [4] 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.
• [5] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [6] 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.
• [7] Mitochondrial effects of estrogen are mediated by estrogen receptor alpha in brain endothelial cells. J Pharmacol Exp Ther. 2008 Jun;325(3):782-90. doi: 10.1124/jpet.107.134072. Epub 2008 Mar 19.
• [8] 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.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] Proteomic and functional analyses reveal a dual molecular mechanism underlying arsenic-induced apoptosis in human multiple myeloma cells. J Proteome Res. 2009 Jun;8(6):3006-19.
• [11] 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.
• [12] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [13] Linalool is a PPARalpha ligand that reduces plasma TG levels and rewires the hepatic transcriptome and plasma metabolome. J Lipid Res. 2014 Jun;55(6):1098-110.
• [14] Label-free quantitative proteomic analysis identifies the oncogenic role of FOXA1 in BaP-transformed 16HBE cells. Toxicol Appl Pharmacol. 2020 Sep 15;403:115160. doi: 10.1016/j.taap.2020.115160. Epub 2020 Jul 25.
• [15] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [16] 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.
• [17] G209A mutant alpha synuclein expression specifically enhances dopamine induced oxidative damage. Neurochem Int. 2004 Oct;45(5):669-76. doi: 10.1016/j.neuint.2004.03.029.
• [18] Effect of soluble nickel on cellular energy metabolism in A549 cells. Exp Biol Med (Maywood). 2006 Oct;231(9):1474-80. doi: 10.1177/153537020623100905.
• [19] Manganese antagonizes iron blocking mitochondrial aconitase expression in human prostate carcinoma cells. Asian J Androl. 2006 May;8(3):307-15. doi: 10.1111/j.1745-7262.2006.00139.x.