Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1AZK6R)

• DOT Name: 2-oxoglutarate dehydrogenase-like, mitochondrial (OGDHL)
• Synonyms: EC 1.2.4.2; 2-oxoglutarate dehydrogenase complex component E1-like; OGDC-E1-like; Alpha-ketoglutarate dehydrogenase-like
• Gene Name: OGDHL
• Related Disease:
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Breast cancer
  Breast carcinoma
  Neoplasm
  Pancreatic cancer
  Yoon-Bellen neurodevelopmental syndrome
  Colorectal carcinoma
  Alzheimer disease
  Eosinophilic esophagitis
• UniProt ID: OGDHL_HUMAN
• EC Number: 1.2.4.2
• Pfam ID: PF16078 ; PF00676 ; PF16870 ; PF02779
• Sequence:
  MSQLRLLPSRLGVQAARLLAAHDVPVFGWRSRSSGPPATFPSSKGGGGSSYMEEMYFAWL
  ENPQSVHKSWDSFFREASEEAFSGSAQPRPPSVVHESRSAVSSRTKTSKLVEDHLAVQSL
  IRAYQIRGHHVAQLDPLGILDADLDSFVPSDLITTIDKLAFYDLQEADLDKEFQLPTTTF
  IGGSENTLSLREIIRRLENTYCQHIGLEFMFINDVEQCQWIRQKFETPGVMQFSSEEKRT
  LLARLVRSMRFEDFLARKWSSEKRFGLEGCEVMIPALKTIIDKSSEMGIENVILGMPHRG
  RLNVLANVIRKDLEQIFCQFDPKLEAADEGSGDVKYHLGMYHERINRVTNRNITLSLVAN
  PSHLEAVDPVVQGKTKAEQFYRGDAQGKKVMSILVHGDAAFAGQGVVYETFHLSDLPSYT
  TNGTVHVVVNNQIGFTTDPRMARSSPYPTDVARVVNAPIFHVNADDPEAVIYVCSVAAEW
  RNTFNKDVVVDLVCYRRRGHNEMDEPMFTQPLMYKQIHRQVPVLKKYADKLIAEGTVTLQ
  EFEEEIAKYDRICEEAYGRSKDKKILHIKHWLDSPWPGFFNVDGEPKSMTCPATGIPEDM
  LTHIGSVASSVPLEDFKIHTGLSRILRGRADMTKNRTVDWALAEYMAFGSLLKEGIHVRL
  SGQDVERGTFSHRHHVLHDQEVDRRTCVPMNHLWPDQAPYTVCNSSLSEYGVLGFELGYA
  MASPNALVLWEAQFGDFHNTAQCIIDQFISTGQAKWVRHNGIVLLLPHGMEGMGPEHSSA
  RPERFLQMSNDDSDAYPAFTKDFEVSQLYDCNWIVVNCSTPANYFHVLRRQILLPFRKPL
  IIFTPKSLLRHPEAKSSFDQMVSGTSFQRVIPEDGAAARAPEQVQRLIFCTGKVYYDLVK
  ERSSQDLEEKVAITRLEQISPFPFDLIKQEAEKYPGAELAWCQEEHKNMGYYDYISPRFM
  TILRRARPIWYVGRDPAAAPATGNRNTHLVSLKKFLDTAFNLQAFEGKTF
• Function: 2-oxoglutarate dehydrogenase (E1-like) component of the 2-oxoglutarate dehydrogenase multienzyme complex (OGDHC) which mediates the decarboxylation of alpha-ketoglutarate in the tricarboxylic acid cycle. The OGDHC complex catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO(2) while reducing NAD(+) to NADH. The OGDHC complex is mainly active in the mitochondrion. Involved in the inhibition of cell proliferation and in apoptosis.
• Tissue Specificity: Expressed in the brain and the liver.
• KEGG Pathway:
  Citrate cycle (TCA cycle) (hsa00020)
  Lipoic acid metabolism (hsa00785)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  2-Oxocarboxylic acid metabolism (hsa01210)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Definitive	Altered Expression	[1]
Liver cancer	DISDE4BI	Definitive	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[3]
Yoon-Bellen neurodevelopmental syndrome	DISJS0WU	Strong	Autosomal recessive	[4]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[5]
Alzheimer disease	DISF8S70	Limited	Biomarker	[6]
Eosinophilic esophagitis	DISR8WSB	Limited	Biomarker	[7]

12 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 2-oxoglutarate dehydrogenase-like, mitochondrial (OGDHL).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 2-oxoglutarate dehydrogenase-like, mitochondrial (OGDHL).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 2-oxoglutarate dehydrogenase-like, mitochondrial (OGDHL).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 2-oxoglutarate dehydrogenase-like, mitochondrial (OGDHL).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 2-oxoglutarate dehydrogenase-like, mitochondrial (OGDHL).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of 2-oxoglutarate dehydrogenase-like, mitochondrial (OGDHL).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 2-oxoglutarate dehydrogenase-like, mitochondrial (OGDHL).	[14]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of 2-oxoglutarate dehydrogenase-like, mitochondrial (OGDHL).	[15]
Menadione	DMSJDTY	Approved	Menadione affects the expression of 2-oxoglutarate dehydrogenase-like, mitochondrial (OGDHL).	[16]
Methamphetamine	DMPM4SK	Approved	Methamphetamine increases the expression of 2-oxoglutarate dehydrogenase-like, mitochondrial (OGDHL).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of 2-oxoglutarate dehydrogenase-like, mitochondrial (OGDHL).	[18]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of 2-oxoglutarate dehydrogenase-like, mitochondrial (OGDHL).	[20]

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 increases the methylation of 2-oxoglutarate dehydrogenase-like, mitochondrial (OGDHL).	[19]

References

• [1] OGDHL Expression as a Prognostic Biomarker for Liver Cancer Patients.Dis Markers. 2019 Oct 17;2019:9037131. doi: 10.1155/2019/9037131. eCollection 2019.
• [2] Discovery of rare coding variants in OGDHL and BRCA2 in relation to breast cancer risk in Chinese women.Int J Cancer. 2020 Apr 15;146(8):2175-2181. doi: 10.1002/ijc.32825. Epub 2019 Dec 27.
• [3] A Novel Oxoglutarate Dehydrogenase-Like Mediated miR-214/TWIST1 Negative Feedback Loop Inhibits Pancreatic Cancer Growth and Metastasis.Clin Cancer Res. 2019 Sep 1;25(17):5407-5421. doi: 10.1158/1078-0432.CCR-18-4113. Epub 2019 Jun 7.
• [4] Bi-allelic variants in OGDHL cause a neurodevelopmental spectrum disease featuring epilepsy, hearing loss, visual impairment, and ataxia. Am J Hum Genet. 2021 Dec 2;108(12):2368-2384. doi: 10.1016/j.ajhg.2021.11.003. Epub 2021 Nov 19.
• [5] Aberrant hypermethylation of OGDHL gene promoter in sporadic colorectal cancer.Curr Probl Cancer. 2020 Feb;44(1):100471. doi: 10.1016/j.currproblcancer.2019.03.001. Epub 2019 Mar 16.
• [6] Alternative cleavage and polyadenylation of genes associated with protein turnover and mitochondrial function are deregulated in Parkinson's, Alzheimer's and ALS disease.BMC Med Genomics. 2019 May 9;12(1):60. doi: 10.1186/s12920-019-0509-4.
• [7] Whole-exome sequencing uncovers oxidoreductases DHTKD1 and OGDHL as linkers between mitochondrial dysfunction and eosinophilic esophagitis.JCI Insight. 2018 Apr 19;3(8):e99922. doi: 10.1172/jci.insight.99922. eCollection 2018 Apr 19.
• [8] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [9] 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.
• [10] 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.
• [11] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [16] 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.
• [17] Methamphetamine alters the normal progression by inducing cell cycle arrest in astrocytes. PLoS One. 2014 Oct 7;9(10):e109603.
• [18] 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.
• [19] 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.
• [20] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.