Details of Drug Off-Target (DOT)

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

• DOT Name: 2-oxoglutarate dehydrogenase complex component E1 (OGDH)
• Synonyms: E1o; OGDC-E1; OGDH-E1; EC 1.2.4.2; 2-oxoglutarate dehydrogenase, mitochondrial; Alpha-ketoglutarate dehydrogenase; Alpha-KGDH-E1; Thiamine diphosphate (ThDP)-dependent 2-oxoglutarate dehydrogenase
• Gene Name: OGDH
• Related Disease: Oxoglutaricaciduria
• UniProt ID: ODO1_HUMAN
• PDB ID: 3ERY; 7WGR
• EC Number: 1.2.4.2
• Pfam ID: PF16078 ; PF00676 ; PF16870 ; PF02779
• Sequence:
  MFHLRTCAAKLRPLTASQTVKTFSQNRPAAARTFQQIRCYSAPVAAEPFLSGTSSNYVEE
  MYCAWLENPKSVHKSWDIFFRNTNAGAPPGTAYQSPLPLSRGSLAAVAHAQSLVEAQPNV
  DKLVEDHLAVQSLIRAYQIRGHHVAQLDPLGILDADLDSSVPADIISSTDKLGFYGLDES
  DLDKVFHLPTTTFIGGQESALPLREIIRRLEMAYCQHIGVEFMFINDLEQCQWIRQKFET
  PGIMQFTNEEKRTLLARLVRSTRFEEFLQRKWSSEKRFGLEGCEVLIPALKTIIDKSSEN
  GVDYVIMGMPHRGRLNVLANVIRKELEQIFCQFDSKLEAADEGSGDVKYHLGMYHRRINR
  VTDRNITLSLVANPSHLEAADPVVMGKTKAEQFYCGDTEGKKVMSILLHGDAAFAGQGIV
  YETFHLSDLPSYTTHGTVHVVVNNQIGFTTDPRMARSSPYPTDVARVVNAPIFHVNSDDP
  EAVMYVCKVAAEWRSTFHKDVVVDLVCYRRNGHNEMDEPMFTQPLMYKQIRKQKPVLQKY
  AELLVSQGVVNQPEYEEEISKYDKICEEAFARSKDEKILHIKHWLDSPWPGFFTLDGQPR
  SMSCPSTGLTEDILTHIGNVASSVPVENFTIHGGLSRILKTRGEMVKNRTVDWALAEYMA
  FGSLLKEGIHIRLSGQDVERGTFSHRHHVLHDQNVDKRTCIPMNHLWPNQAPYTVCNSSL
  SEYGVLGFELGFAMASPNALVLWEAQFGDFHNTAQCIIDQFICPGQAKWVRQNGIVLLLP
  HGMEGMGPEHSSARPERFLQMCNDDPDVLPDLKEANFDINQLYDCNWVVVNCSTPGNFFH
  VLRRQILLPFRKPLIIFTPKSLLRHPEARSSFDEMLPGTHFQRVIPEDGPAAQNPENVKR
  LLFCTGKVYYDLTRERKARDMVGQVAITRIEQLSPFPFDLLLKEVQKYPNAELAWCQEEH
  KNQGYYDYVKPRLRTTISRAKPVWYAGRDPAAAPATGNKKTHLTELQRLLDTAFDLDVFK
  NFS
• Function: 2-oxoglutarate dehydrogenase (E1o) component of the 2-oxoglutarate dehydrogenase complex (OGDHC). Participates in the first step, rate limiting for the overall conversion of 2-oxoglutarate to succinyl-CoA and CO(2) catalyzed by the whole OGDHC. Catalyzes the irreversible decarboxylation of 2-oxoglutarate (alpha-ketoglutarate) via the thiamine diphosphate (ThDP) cofactor and subsequent transfer of the decarboxylated acyl intermediate on an oxidized dihydrolipoyl group that is covalently amidated to the E2 enzyme (dihydrolipoyllysine-residue succinyltransferase or DLST). Plays a key role in the Krebs (citric acid) cycle, which is a common pathway for oxidation of fuel molecules, including carbohydrates, fatty acids, and amino acids. Can catalyze the decarboxylation of 2-oxoadipate in vitro, but at a much lower rate than 2-oxoglutarate. 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)
  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:HS02832-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
Oxoglutaricaciduria	DISSCY93	Strong	Autosomal recessive	[1]

17 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of 2-oxoglutarate dehydrogenase complex component E1 (OGDH).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of 2-oxoglutarate dehydrogenase complex component E1 (OGDH).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of 2-oxoglutarate dehydrogenase complex component E1 (OGDH).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of 2-oxoglutarate dehydrogenase complex component E1 (OGDH).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 2-oxoglutarate dehydrogenase complex component E1 (OGDH).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the activity of 2-oxoglutarate dehydrogenase complex component E1 (OGDH).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of 2-oxoglutarate dehydrogenase complex component E1 (OGDH).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of 2-oxoglutarate dehydrogenase complex component E1 (OGDH).	[9]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of 2-oxoglutarate dehydrogenase complex component E1 (OGDH).	[11]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of 2-oxoglutarate dehydrogenase complex component E1 (OGDH).	[12]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of 2-oxoglutarate dehydrogenase complex component E1 (OGDH).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of 2-oxoglutarate dehydrogenase complex component E1 (OGDH).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of 2-oxoglutarate dehydrogenase complex component E1 (OGDH).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 2-oxoglutarate dehydrogenase complex component E1 (OGDH).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of 2-oxoglutarate dehydrogenase complex component E1 (OGDH).	[17]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of 2-oxoglutarate dehydrogenase complex component E1 (OGDH).	[18]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone affects the splicing of 2-oxoglutarate dehydrogenase complex component E1 (OGDH).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of 2-oxoglutarate dehydrogenase complex component E1 (OGDH).	[10]

References

• [1] 2-ketoglutarate dehydrogenase deficiency with intermittent 2-ketoglutaric aciduria. Neuropediatrics. 2000 Feb;31(1):35-8. doi: 10.1055/s-2000-15295.
• [2] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [3] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [4] 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.
• [5] Expression Profiling of Human Pluripotent Stem Cell-Derived Cardiomyocytes Exposed to Doxorubicin-Integration and Visualization of Multi-Omics Data. Toxicol Sci. 2018 May 1;163(1):182-195. doi: 10.1093/toxsci/kfy012.
• [6] 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.
• [7] The effects of kahweol, a diterpene present in coffee, on the mitochondria of the human neuroblastoma SH-SY5Y cells exposed to hydrogen peroxide. Toxicol In Vitro. 2019 Dec;61:104601. doi: 10.1016/j.tiv.2019.104601. Epub 2019 Jul 12.
• [8] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [9] 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.
• [10] 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.
• [11] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [12] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [13] 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.
• [14] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [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] 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.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] Ochratoxin A induces reprogramming of glucose metabolism by switching energy metabolism from oxidative phosphorylation to glycolysis in human gastric epithelium GES-1 cells in vitro. Toxicol Lett. 2020 Oct 15;333:232-241. doi: 10.1016/j.toxlet.2020.08.008. Epub 2020 Aug 22.
• [19] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.