Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW6C712)

• DOT Name: L-2-hydroxyglutarate dehydrogenase, mitochondrial (L2HGDH)
• Synonyms: EC 1.1.99.2; Duranin
• Gene Name: L2HGDH
• Related Disease:
  L-2-hydroxyglutaric aciduria
  Mitochondrial disease
  2-hydroxyglutaric aciduria
  Adult glioblastoma
  Brain neoplasm
  Clear cell renal carcinoma
  Congenital nervous system disorder
  D-2-hydroxyglutaric aciduria
  D-2-hydroxyglutaric aciduria 1
  Epilepsy
  Metabolic disorder
  Renal cell carcinoma
  Intellectual disability
  Glioblastoma multiforme
  Dystonia
• UniProt ID: L2HDH_HUMAN
• EC Number: 1.1.99.2
• Pfam ID: PF01266
• Sequence:
  MVPALRYLVGACGRARGLFAGGSPGACGFASGRPRPLCGGSRSASTSSFDIVIVGGGIVG
  LASARALILRHPSLSIGVLEKEKDLAVHQTGHNSGVIHSGIYYKPESLKAKLCVQGAALL
  YEYCQQKGISYKQCGKLIVAVEQEEIPRLQALYEKGLQNGVPGLRLIQQEDIKKKEPYCR
  GLMAIDCPHTGIVDYRQVALSFAQDFQEAGGSVLTNFEVKGIEMAKESPSRSIDGMQYPI
  VIKNTKGEEIRCQYVVTCAGLYSDRISELSGCTPDPRIVPFRGDYLLLKPEKCYLVKGNI
  YPVPDSRFPFLGVHFTPRMDGSIWLGPNAVLAFKREGYRPFDFSATDVMDIIINSGLIKL
  ASQNFSYGVTEMYKACFLGATVKYLQKFIPEITISDILRGPAGVRAQALDRDGNLVEDFV
  FDAGVGDIGNRILHVRNAPSPAATSSIAISGMIADEVQQRFEL
• Tissue Specificity: Widely expressed. Highly expressed in brain, testis and muscle. Expressed to a lower extent in lymphocytes, fibroblasts, keratinocytes, placenta, bladder, small intestine, liver and bone marrow.
• KEGG Pathway:
  Butanoate metabolism (hsa00650)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Interconversion of 2-oxoglutarate and 2-hydroxyglutarate (R-HSA-880009)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
L-2-hydroxyglutaric aciduria	DIS5FY7E	Definitive	Autosomal recessive	[1]
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[2]
2-hydroxyglutaric aciduria	DIS4P821	Strong	Genetic Variation	[3]
Adult glioblastoma	DISVP4LU	Strong	Genetic Variation	[4]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[5]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[6]
Congenital nervous system disorder	DIS2BIP8	Strong	Biomarker	[7]
D-2-hydroxyglutaric aciduria	DIS3JMXH	Strong	Altered Expression	[8]
D-2-hydroxyglutaric aciduria 1	DISFYZD5	Strong	Biomarker	[9]
Epilepsy	DISBB28L	Strong	Biomarker	[7]
Metabolic disorder	DIS71G5H	Strong	Genetic Variation	[10]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[11]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[12]
Glioblastoma multiforme	DISK8246	Disputed	Genetic Variation	[4]
Dystonia	DISJLFGW	Limited	Biomarker	[13]

9 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 L-2-hydroxyglutarate dehydrogenase, mitochondrial (L2HGDH).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of L-2-hydroxyglutarate dehydrogenase, mitochondrial (L2HGDH).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of L-2-hydroxyglutarate dehydrogenase, mitochondrial (L2HGDH).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of L-2-hydroxyglutarate dehydrogenase, mitochondrial (L2HGDH).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of L-2-hydroxyglutarate dehydrogenase, mitochondrial (L2HGDH).	[18]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of L-2-hydroxyglutarate dehydrogenase, mitochondrial (L2HGDH).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of L-2-hydroxyglutarate dehydrogenase, mitochondrial (L2HGDH).	[20]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of L-2-hydroxyglutarate dehydrogenase, mitochondrial (L2HGDH).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of L-2-hydroxyglutarate dehydrogenase, mitochondrial (L2HGDH).	[19]

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 L-2-hydroxyglutarate dehydrogenase, mitochondrial (L2HGDH).	[22]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Two novel L2HGDH mutations identified in a rare Chinese family with L-2-hydroxyglutaric aciduria.BMC Med Genet. 2018 Sep 14;19(1):167. doi: 10.1186/s12881-018-0675-9.
• [4] Screen for IDH1, IDH2, IDH3, D2HGDH and L2HGDH mutations in glioblastoma.PLoS One. 2011;6(5):e19868. doi: 10.1371/journal.pone.0019868. Epub 2011 May 23.
• [5] L-2-hydroxyglutaric aciduria and brain tumors in children with mutations in the L2HGDH gene: neuroimaging findings.Neuropediatrics. 2008 Apr;39(2):119-22. doi: 10.1055/s-2008-1081217.
• [6] Ascorbic acid-induced TET activation mitigates adverse hydroxymethylcytosine loss in renal cell carcinoma.J Clin Invest. 2019 Mar 4;129(4):1612-1625. doi: 10.1172/JCI98747. eCollection 2019 Mar 4.
• [7] L-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1.Hum Mol Genet. 2004 Nov 15;13(22):2803-11. doi: 10.1093/hmg/ddh300. Epub 2004 Sep 22.
• [8] Measurement of D: -2-hydroxyglutarate dehydrogenase activity in cell homogenates derived from D: -2-hydroxyglutaric aciduria patients.J Inherit Metab Dis. 2009 Apr;32(2):264-8. doi: 10.1007/s10545-009-1104-1. Epub 2009 Mar 13.
• [9] D-2-hydroxyglutaric aciduria and glutaric aciduria type 1 in siblings: coincidence, or linked disorders?.Neuropediatrics. 2004 Jun;35(3):151-6. doi: 10.1055/s-2004-817905.
• [10] Clinical, genetic and magnetic resonance findings in an Italian patient affected by L-2-hydroxyglutaric aciduria.Neurol Sci. 2011 Feb;32(1):95-9. doi: 10.1007/s10072-010-0416-0. Epub 2010 Sep 22.
• [11] Biochemical and Epigenetic Insights into L-2-Hydroxyglutarate, a Potential Therapeutic Target in Renal Cancer.Clin Cancer Res. 2018 Dec 15;24(24):6433-6446. doi: 10.1158/1078-0432.CCR-18-1727. Epub 2018 Aug 14.
• [12] White matter abnormalities in an adult patient with l-2-hydroxyglutaric aciduria.Brain Dev. 2016 Jan;38(1):142-4. doi: 10.1016/j.braindev.2015.04.012. Epub 2015 May 14.
• [13] L-2-hydroxyglutaric aciduria: clinical and molecular study in three Tunisian families. Identification of a new mutation and inter-familial phenotype variability.J Inherit Metab Dis. 2008 Dec;31 Suppl 2:S375-9. doi: 10.1007/s10545-008-0934-6. Epub 2008 Sep 13.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [20] 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.
• [21] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [22] 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.