Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBDF9HJ)

• DOT Name: Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial (DLST)
• Synonyms: EC 2.3.1.61; 2-oxoglutarate dehydrogenase complex component E2; OGDC-E2; Dihydrolipoamide succinyltransferase component of 2-oxoglutarate dehydrogenase complex; E2K
• Gene Name: DLST
• Related Disease:
  Androgen insensitivity syndrome
  Neoplasm
  Paraganglioma
  Pheochromocytoma
  Primary biliary cholangitis
  Prostate cancer
  Prostate carcinoma
  Acute myelogenous leukaemia
  Hereditary pheochromocytoma-paraganglioma
  Paragangliomas 7
  Pyruvate dehydrogenase E1-alpha deficiency
• UniProt ID: ODO2_HUMAN
• PDB ID: 6H05
• EC Number: 2.3.1.61
• Pfam ID: PF00198 ; PF00364
• Sequence:
  MLSRSRCVSRAFSRSLSAFQKGNCPLGRRSLPGVSLCQGPGYPNSRKVVINNSVFSVRFF
  RTTAVCKDDLVTVKTPAFAESVTEGDVRWEKAVGDTVAEDEVVCEIETDKTSVQVPSPAN
  GVIEALLVPDGGKVEGGTPLFTLRKTGAAPAKAKPAEAPAAAAPKAEPTAAAVPPPAAPI
  PTQMPPVPSPSQPPSGKPVSAVKPTVAPPLAEPGAGKGLRSEHREKMNRMRQRIAQRLKE
  AQNTCAMLTTFNEIDMSNIQEMRARHKEAFLKKHNLKLGFMSAFVKASAFALQEQPVVNA
  VIDDTTKEVVYRDYIDISVAVATPRGLVVPVIRNVEAMNFADIERTITELGEKARKNELA
  IEDMDGGTFTISNGGVFGSLFGTPIINPPQSAILGMHGIFDRPVAIGGKVEVRPMMYVAL
  TYDHRLIDGREAVTFLRKIKAAVEDPRVLLLDL
• Function: Dihydrolipoamide succinyltransferase (E2) component of the 2-oxoglutarate dehydrogenase complex. The 2-oxoglutarate dehydrogenase complex catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO(2). The 2-oxoglutarate dehydrogenase complex is mainly active in the mitochondrion. A fraction of the 2-oxoglutarate dehydrogenase complex also localizes in the nucleus and is required for lysine succinylation of histones: associates with KAT2A on chromatin and provides succinyl-CoA to histone succinyltransferase KAT2A.
• KEGG Pathway:
  Citrate cycle (TCA cycle) (hsa00020)
  Lysine degradation (hsa00310)
  Tryptophan metabolism (hsa00380)
  Lipoic acid metabolism (hsa00785)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  2-Oxocarboxylic acid metabolism (hsa01210)
• Reactome Pathway:
  Lysine catabolism (R-HSA-71064)
  Citric acid cycle (TCA cycle) (R-HSA-71403)
  Glyoxylate metabolism and glycine degradation (R-HSA-389661)
• BioCyc Pathway: MetaCyc:HS04324-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Androgen insensitivity syndrome	DISUZBBO	Strong	Genetic Variation	[1]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[2]
Paraganglioma	DIS2XXH5	Strong	Genetic Variation	[2]
Pheochromocytoma	DIS56IFV	Strong	Genetic Variation	[2]
Primary biliary cholangitis	DIS43E0O	Strong	Biomarker	[3]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[1]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[1]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[4]
Hereditary pheochromocytoma-paraganglioma	DISP9K7L	Supportive	Autosomal dominant	[5]
Paragangliomas 7	DIS92ABC	Limited	Autosomal dominant	[6]
Pyruvate dehydrogenase E1-alpha deficiency	DISZ6WMJ	No Known	Autosomal recessive	[7]

11 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 Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial (DLST).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial (DLST).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial (DLST).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial (DLST).	[11]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial (DLST).	[12]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial (DLST).	[9]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial (DLST).	[13]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial (DLST).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial (DLST).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial (DLST).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial (DLST).	[16]

References

• [1] Androgen receptor mutations identified in prostate cancer and androgen insensitivity syndrome display aberrant ART-27 coactivator function.Mol Endocrinol. 2005 Sep;19(9):2273-82. doi: 10.1210/me.2005-0134. Epub 2005 May 26.
• [2] Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas.Am J Hum Genet. 2019 Apr 4;104(4):651-664. doi: 10.1016/j.ajhg.2019.02.017. Epub 2019 Mar 28.
• [3] Promiscuous T cells selected by Escherichia coli: OGDC-E2 in primary biliary cirrhosis.J Autoimmun. 2003 May;20(3):255-63. doi: 10.1016/s0896-8411(03)00024-6.
• [4] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [5] Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas. Am J Hum Genet. 2019 May 2;104(5):1008-1010. doi: 10.1016/j.ajhg.2019.04.010.
• [6] Germline DLST Variants Promote Epigenetic Modifications in Pheochromocytoma-Paraganglioma. J Clin Endocrinol Metab. 2021 Jan 23;106(2):459-471. doi: 10.1210/clinem/dgaa819.
• [7] Loss of dihydrolipoyl succinyltransferase (DLST) leads to reduced resting heart rate in the zebrafish. Basic Res Cardiol. 2015 Mar;110(2):14. doi: 10.1007/s00395-015-0468-7. Epub 2015 Feb 20.
• [8] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [9] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [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] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [12] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [13] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [14] 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.
• [15] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [16] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.