Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF3GGYY)

• DOT Name: Glutamate dehydrogenase 2, mitochondrial (GLUD2)
• Synonyms: GDH 2; EC 1.4.1.3
• Gene Name: GLUD2
• Related Disease:
  Type-1/2 diabetes
  Epilepsy
  Glioma
  Schizophrenia
  Advanced cancer
  Parkinson disease
  Small lymphocytic lymphoma
  Adult glioblastoma
  Glioblastoma multiforme
  Neoplasm
  Neuroblastoma
  Rett syndrome
• UniProt ID: DHE4_HUMAN
• PDB ID: 6G2U
• EC Number: 1.4.1.3
• Pfam ID: PF00208 ; PF02812
• Sequence:
  MYRYLAKALLPSRAGPAALGSAANHSAALLGRGRGQPAAASQPGLALAARRHYSELVADR
  EDDPNFFKMVEGFFDRGASIVEDKLVKDLRTQESEEQKRNRVRGILRIIKPCNHVLSLSF
  PIRRDDGSWEVIEGYRAQHSQHRTPCKGGIRYSTDVSVDEVKALASLMTYKCAVVDVPFG
  GAKAGVKINPKNYTENELEKITRRFTMELAKKGFIGPGVDVPAPDMNTGEREMSWIADTY
  ASTIGHYDINAHACVTGKPISQGGIHGRISATGRGVFHGIENFINEASYMSILGMTPGFR
  DKTFVVQGFGNVGLHSMRYLHRFGAKCIAVGESDGSIWNPDGIDPKELEDFKLQHGSILG
  FPKAKPYEGSILEVDCDILIPAATEKQLTKSNAPRVKAKIIAEGANGPTTPEADKIFLER
  NILVIPDLYLNAGGVTVSYFEWLKNLNHVSYGRLTFKYERDSNYHLLLSVQESLERKFGK
  HGGTIPIVPTAEFQDSISGASEKDIVHSALAYTMERSARQIMHTAMKYNLGLDLRTAAYV
  NAIEKVFKVYSEAGVTFT
• Function: Important for recycling the chief excitatory neurotransmitter, glutamate, during neurotransmission.
• Tissue Specificity: Expressed in retina, testis and, at a lower level, brain.
• KEGG Pathway:
  Arginine biosynthesis (hsa00220)
  Alanine, aspartate and glutamate metabolism (hsa00250)
  Nitrogen metabolism (hsa00910)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  Necroptosis (hsa04217)
  Proximal tubule bicarbo.te reclamation (hsa04964)
• Reactome Pathway:
  Glutamate and glutamine metabolism (R-HSA-8964539)
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)
• BioCyc Pathway: MetaCyc:HS00018-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Type-1/2 diabetes	DISIUHAP	Definitive	Biomarker	[1]
Epilepsy	DISBB28L	Strong	Biomarker	[2]
Glioma	DIS5RPEH	Strong	Biomarker	[3]
Schizophrenia	DISSRV2N	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[5]
Parkinson disease	DISQVHKL	moderate	Genetic Variation	[6]
Small lymphocytic lymphoma	DIS30POX	moderate	Altered Expression	[7]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[8]
Glioblastoma multiforme	DISK8246	Limited	Altered Expression	[8]
Neoplasm	DISZKGEW	Limited	Biomarker	[9]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[10]
Rett syndrome	DISGG5UV	Limited	Altered Expression	[11]

16 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 Glutamate dehydrogenase 2, mitochondrial (GLUD2).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glutamate dehydrogenase 2, mitochondrial (GLUD2).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Glutamate dehydrogenase 2, mitochondrial (GLUD2).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glutamate dehydrogenase 2, mitochondrial (GLUD2).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Glutamate dehydrogenase 2, mitochondrial (GLUD2).	[16]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Glutamate dehydrogenase 2, mitochondrial (GLUD2).	[17]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Glutamate dehydrogenase 2, mitochondrial (GLUD2).	[18]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Glutamate dehydrogenase 2, mitochondrial (GLUD2).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Glutamate dehydrogenase 2, mitochondrial (GLUD2).	[19]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Glutamate dehydrogenase 2, mitochondrial (GLUD2).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Glutamate dehydrogenase 2, mitochondrial (GLUD2).	[21]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Glutamate dehydrogenase 2, mitochondrial (GLUD2).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Glutamate dehydrogenase 2, mitochondrial (GLUD2).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Glutamate dehydrogenase 2, mitochondrial (GLUD2).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Glutamate dehydrogenase 2, mitochondrial (GLUD2).	[25]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Glutamate dehydrogenase 2, mitochondrial (GLUD2).	[26]

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 Glutamate dehydrogenase 2, mitochondrial (GLUD2).	[22]

References

• [1] Transgenic expression of the positive selected human GLUD2 gene improves in vivo glucose homeostasis by regulating basic insulin secretion.Metabolism. 2019 Nov;100:153958. doi: 10.1016/j.metabol.2019.153958. Epub 2019 Aug 7.
• [2] Epilepsy with myoclonic atonic seizures and chronic cerebellar symptoms associated with antibodies against glutamate receptors N2B and D2 in serum and cerebrospinal fluid.Epileptic Disord. 2017 Mar 1;19(1):94-98. doi: 10.1684/epd.2017.0895.
• [3] Adaptive Evolution of the GDH2 Allosteric Domain Promotes Gliomagenesis by Resolving IDH1(R132H)-Induced Metabolic Liabilities.Cancer Res. 2018 Jan 1;78(1):36-50. doi: 10.1158/0008-5472.CAN-17-1352. Epub 2017 Nov 2.
• [4] GluD1, linked to schizophrenia, controls the burst firing of dopamine neurons.Mol Psychiatry. 2018 Mar;23(3):691-700. doi: 10.1038/mp.2017.137. Epub 2017 Jul 11.
• [5] Glutamate production from ammonia via glutamate dehydrogenase 2 activity supports cancer cell proliferation under glutamine depletion.Biochem Biophys Res Commun. 2018 Jan 1;495(1):761-767. doi: 10.1016/j.bbrc.2017.11.088. Epub 2017 Nov 14.
• [6] Deregulation of glutamate dehydrogenase in human neurologic disorders.J Neurosci Res. 2013 Aug;91(8):1007-17. doi: 10.1002/jnr.23176. Epub 2013 Mar 6.
• [7] Glutamate dehydrogenase activity in lymphocytes of B-cell chronic lymphocytic leukaemia patients.Clin Biochem. 2009 Nov;42(16-17):1677-84. doi: 10.1016/j.clinbiochem.2009.08.003. Epub 2009 Aug 13.
• [8] Mitochondrial enzyme GLUD2 plays a critical role in glioblastoma progression.EBioMedicine. 2018 Nov;37:56-67. doi: 10.1016/j.ebiom.2018.10.008. Epub 2018 Oct 9.
• [9] Widening Spectrum of Cellular and Subcellular Expression of Human GLUD1 and GLUD2 Glutamate Dehydrogenases Suggests Novel Functions.Neurochem Res. 2017 Jan;42(1):92-107. doi: 10.1007/s11064-016-1986-x. Epub 2016 Jul 16.
• [10] Glutamate receptor 2 serum antibodies in pediatric opsoclonus myoclonus ataxia syndrome.Neurology. 2018 Aug 21;91(8):e714-e723. doi: 10.1212/WNL.0000000000006035. Epub 2018 Jul 25.
• [11] Evaluation of two X chromosomal candidate genes for Rett syndrome: glutamate dehydrogenase-2 (GLUD2) and rab GDP-dissociation inhibitor (GDI1).Am J Med Genet. 1998 Jun 30;78(2):169-72.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] 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.
• [14] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [15] 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.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] Protein expression profiling identifies molecular targets of quercetin as a major dietary flavonoid in human colon cancer cells. Proteomics. 2004 Jul;4(7):2160-74.
• [18] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [19] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [20] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [25] 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.
• [26] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.