Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLHXW69)

• DOT Name: D-2-hydroxyglutarate dehydrogenase, mitochondrial (D2HGDH)
• Synonyms: EC 1.1.99.39
• Gene Name: D2HGDH
• Related Disease:
  2-hydroxyglutaric aciduria
  Advanced cancer
  B-cell lymphoma
  Colon cancer
  Colon carcinoma
  D-2-hydroxyglutaric aciduria 1
  D-2-hydroxyglutaric aciduria 2
  Glioblastoma multiforme
  Inborn disorder of amino acid metabolism
  Metabolic disorder
  Peripheral neuropathy
  Ulcerative colitis
  D-2-hydroxyglutaric aciduria
  Asthma
• UniProt ID: D2HDH_HUMAN
• PDB ID: 6LPN; 6LPP; 6LPQ; 6LPT; 6LPU; 6LPX
• EC Number: 1.1.99.39
• Pfam ID: PF02913 ; PF01565
• Sequence:
  MLPRRPLAWPAWLLRGAPGAAGSWGRPVGPLARRGCCSAPGTPEVPLTRERYPVRRLPFS
  TVSKQDLAAFERIVPGGVVTDPEALQAPNVDWLRTLRGCSKVLLRPRTSEEVSHILRHCH
  ERNLAVNPQGGNTGMVGGSVPVFDEIILSTARMNRVLSFHSVSGILVCQAGCVLEELSRY
  VEERDFIMPLDLGAKGSCHIGGNVATNAGGLRFLRYGSLHGTVLGLEVVLADGTVLDCLT
  SLRKDNTGYDLKQLFIGSEGTLGIITTVSILCPPKPRAVNVAFLGCPGFAEVLQTFSTCK
  GMLGEILSAFEFMDAVCMQLVGRHLHLASPVQESPFYVLIETSGSNAGHDAEKLGHFLEH
  ALGSGLVTDGTMATDQRKVKMLWALRERITEALSRDGYVYKYDLSLPVERLYDIVTDLRA
  RLGPHAKHVVGYGHLGDGNLHLNVTAEAFSPSLLAALEPHVYEWTAGQQGSVSAEHGVGF
  RKRDVLGYSKPPGALQLMQQLKALLDPKGILNPYKTLPSQA
• Function: Catalyzes the oxidation of D-2-hydroxyglutarate (D-2-HG) to alpha-ketoglutarate. Also catalyzes the oxidation of other D-2-hydroxyacids, such as D-malate (D-MAL) and D-lactate (D-LAC). Exhibits high activities towards D-2-HG and D-MAL but a very weak activity towards D-LAC.
• Reactome Pathway: Interconversion of 2-oxoglutarate and 2-hydroxyglutarate (R-HSA-880009)
• BioCyc Pathway: MetaCyc:ENSG00000180902-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
2-hydroxyglutaric aciduria	DIS4P821	Strong	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
B-cell lymphoma	DISIH1YQ	Strong	Genetic Variation	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[2]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[2]
D-2-hydroxyglutaric aciduria 1	DISFYZD5	Strong	Autosomal recessive	[4]
D-2-hydroxyglutaric aciduria 2	DISWXIE7	Strong	Genetic Variation	[5]
Glioblastoma multiforme	DISK8246	Strong	Genetic Variation	[6]
Inborn disorder of amino acid metabolism	DISFWXCM	Strong	Biomarker	[7]
Metabolic disorder	DIS71G5H	Strong	Genetic Variation	[8]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[9]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[2]
D-2-hydroxyglutaric aciduria	DIS3JMXH	Supportive	Autosomal dominant	[10]
Asthma	DISW9QNS	Limited	Genetic Variation	[11]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Alpha-ketoglutaric acid	DM5LFYN	Investigative	D-2-hydroxyglutarate dehydrogenase, mitochondrial (D2HGDH) increases the chemical synthesis of Alpha-ketoglutaric acid.	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of D-2-hydroxyglutarate dehydrogenase, mitochondrial (D2HGDH).	[12]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of D-2-hydroxyglutarate dehydrogenase, mitochondrial (D2HGDH).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of D-2-hydroxyglutarate dehydrogenase, mitochondrial (D2HGDH).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of D-2-hydroxyglutarate dehydrogenase, mitochondrial (D2HGDH).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of D-2-hydroxyglutarate dehydrogenase, mitochondrial (D2HGDH).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of D-2-hydroxyglutarate dehydrogenase, mitochondrial (D2HGDH).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of D-2-hydroxyglutarate dehydrogenase, mitochondrial (D2HGDH).	[18]

References

• [1] D-2-hydroxyglutaric aciduria Type I: Functional analysis of D2HGDH missense variants.Hum Mutat. 2019 Jul;40(7):975-982. doi: 10.1002/humu.23751. Epub 2019 Apr 13.
• [2] Elevated d-2-hydroxyglutarate during colitis drives progression to colorectal cancer.Proc Natl Acad Sci U S A. 2018 Jan 30;115(5):1057-1062. doi: 10.1073/pnas.1712625115. Epub 2018 Jan 16.
• [3] D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2.Nat Commun. 2015 Jul 16;6:7768. doi: 10.1038/ncomms8768.
• [4] Identification of a dehydrogenase acting on D-2-hydroxyglutarate. Biochem J. 2004 Jul 1;381(Pt 1):35-42. doi: 10.1042/BJ20031933.
• [5] Computational approach to unravel the impact of missense mutations of proteins (D2HGDH and IDH2) causing D-2-hydroxyglutaric aciduria 2.Metab Brain Dis. 2018 Oct;33(5):1699-1710. doi: 10.1007/s11011-018-0278-3. Epub 2018 Jul 9.
• [6] 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.
• [7] Mutations in the D-2-hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria. Am J Hum Genet. 2005 Feb;76(2):358-60. doi: 10.1086/427890. Epub 2004 Dec 17.
• [8] Phenotypic heterogeneity in the presentation of D-2-hydroxyglutaric aciduria in monozygotic twins.Mol Genet Metab. 2005 Sep-Oct;86(1-2):200-5. doi: 10.1016/j.ymgme.2005.06.005. Epub 2005 Aug 2.
• [9] Peripheral neuropathy in a patient with D-2-hydroxyglutaric aciduria.J Inherit Metab Dis. 2009 Dec;32 Suppl 1:S21-5. doi: 10.1007/s10545-009-0933-2. Epub 2009 Jan 26.
• [10] Evidence for genetic heterogeneity in D-2-hydroxyglutaric aciduria. Hum Mutat. 2010 Mar;31(3):279-83. doi: 10.1002/humu.21186.
• [11] Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct.Am J Hum Genet. 2019 Apr 4;104(4):665-684. doi: 10.1016/j.ajhg.2019.02.022. Epub 2019 Mar 28.
• [12] 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.
• [13] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [14] 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.
• [15] 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.
• [16] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [17] 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.
• [18] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [19] Mutations in the D-2-hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria. Am J Hum Genet. 2005 Feb;76(2):358-60. doi: 10.1086/427890. Epub 2004 Dec 17.