Details of Drug Off-Target (DOT)

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

DOT Name Glutamate dehydrogenase 1, mitochondrial (GLUD1)
Synonyms GDH 1; EC 1.4.1.3
Gene Name GLUD1
Related Disease
Central diabetes insipidus ( )
Hyperinsulinism-hyperammonemia syndrome ( )
Metabolic disorder ( )
Primary hyperoxaluria ( )
Prostate cancer ( )
Prostate carcinoma ( )
Absence epilepsy ( )
Adult glioblastoma ( )
Beta thalassemia ( )
Beta-thalassemia major ( )
Breast cancer ( )
Breast carcinoma ( )
CHARGE syndrome ( )
Colorectal carcinoma ( )
Epilepsy ( )
Fetal growth restriction ( )
Giardiasis ( )
Glioblastoma multiforme ( )
Glioma ( )
Hepatic encephalopathy ( )
Hoyeraal-Hreidarsson syndrome ( )
Hypoglycemia ( )
Hypotrichosis 1 ( )
Intrahepatic cholangiocarcinoma ( )
Matthew-Wood syndrome ( )
Movement disorder ( )
Neoplasm ( )
Schizophrenia ( )
Temporal lobe epilepsy ( )
Lung cancer ( )
Lung carcinoma ( )
Small lymphocytic lymphoma ( )
Advanced cancer ( )
Hyperinsulinemia ( )
Metastatic malignant neoplasm ( )
Nervous system disease ( )
Pancreatic cancer ( )
Parkinson disease ( )
Rett syndrome ( )
UniProt ID
DHE3_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
PDB ID
1L1F; 1NR1; 6DQG; 7UZM; 8KGY; 8W4J
EC Number
1.4.1.3
Pfam ID
PF00208 ; PF02812
Sequence
MYRYLGEALLLSRAGPAALGSASADSAALLGWARGQPAAAPQPGLALAARRHYSEAVADR
EDDPNFFKMVEGFFDRGASIVEDKLVEDLRTRESEEQKRNRVRGILRIIKPCNHVLSLSF
PIRRDDGSWEVIEGYRAQHSQHRTPCKGGIRYSTDVSVDEVKALASLMTYKCAVVDVPFG
GAKAGVKINPKNYTDNELEKITRRFTMELAKKGFIGPGIDVPAPDMSTGEREMSWIADTY
ASTIGHYDINAHACVTGKPISQGGIHGRISATGRGVFHGIENFINEASYMSILGMTPGFG
DKTFVVQGFGNVGLHSMRYLHRFGAKCIAVGESDGSIWNPDGIDPKELEDFKLQHGSILG
FPKAKPYEGSILEADCDILIPAASEKQLTKSNAPRVKAKIIAEGANGPTTPEADKIFLER
NIMVIPDLYLNAGGVTVSYFEWLKNLNHVSYGRLTFKYERDSNYHLLMSVQESLERKFGK
HGGTIPIVPTAEFQDRISGASEKDIVHSGLAYTMERSARQIMRTAMKYNLGLDLRTAAYV
NAIEKVFKVYNEAGVTFT
Function
Mitochondrial glutamate dehydrogenase that catalyzes the conversion of L-glutamate into alpha-ketoglutarate. Plays a key role in glutamine anaplerosis by producing alpha-ketoglutarate, an important intermediate in the tricarboxylic acid cycle. Plays a role in insulin homeostasis. May be involved in learning and memory reactions by increasing the turnover of the excitatory neurotransmitter glutamate.
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:HS07548-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

39 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Central diabetes insipidus DISJ4P9O Definitive Biomarker [1]
Hyperinsulinism-hyperammonemia syndrome DISP0IHP Definitive Autosomal dominant [2]
Metabolic disorder DIS71G5H Definitive Genetic Variation [3]
Primary hyperoxaluria DIS0L16N Definitive Biomarker [4]
Prostate cancer DISF190Y Definitive Altered Expression [5]
Prostate carcinoma DISMJPLE Definitive Altered Expression [5]
Absence epilepsy DISJPOUD Strong Biomarker [6]
Adult glioblastoma DISVP4LU Strong Posttranslational Modification [7]
Beta thalassemia DIS5RCQK Strong Altered Expression [8]
Beta-thalassemia major DISW06BV Strong Altered Expression [8]
Breast cancer DIS7DPX1 Strong Altered Expression [9]
Breast carcinoma DIS2UE88 Strong Altered Expression [9]
CHARGE syndrome DISKD3CW Strong Genetic Variation [10]
Colorectal carcinoma DIS5PYL0 Strong Biomarker [11]
Epilepsy DISBB28L Strong Genetic Variation [12]
Fetal growth restriction DIS5WEJ5 Strong Altered Expression [13]
Giardiasis DISWUNWK Strong Genetic Variation [14]
Glioblastoma multiforme DISK8246 Strong Biomarker [15]
Glioma DIS5RPEH Strong Altered Expression [16]
Hepatic encephalopathy DISEAKAN Strong Biomarker [17]
Hoyeraal-Hreidarsson syndrome DISAUR8F Strong Genetic Variation [10]
Hypoglycemia DISRCKR7 Strong Genetic Variation [18]
Hypotrichosis 1 DIS0XPER Strong Genetic Variation [10]
Intrahepatic cholangiocarcinoma DIS6GOC8 Strong Biomarker [19]
Matthew-Wood syndrome DISA7HR7 Strong Biomarker [20]
Movement disorder DISOJJ2D Strong Altered Expression [21]
Neoplasm DISZKGEW Strong Biomarker [22]
Schizophrenia DISSRV2N Strong Biomarker [23]
Temporal lobe epilepsy DISNOPXX Strong Biomarker [24]
Lung cancer DISCM4YA moderate Biomarker [25]
Lung carcinoma DISTR26C moderate Biomarker [25]
Small lymphocytic lymphoma DIS30POX moderate Altered Expression [26]
Advanced cancer DISAT1Z9 Limited Posttranslational Modification [7]
Hyperinsulinemia DISIDWT6 Limited Genetic Variation [27]
Metastatic malignant neoplasm DIS86UK6 Limited Biomarker [25]
Nervous system disease DISJ7GGT Limited Genetic Variation [28]
Pancreatic cancer DISJC981 Limited Altered Expression [29]
Parkinson disease DISQVHKL Limited Genetic Variation [30]
Rett syndrome DISGG5UV Limited Biomarker [31]
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⏷ Show the Full List of 39 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate decreases the methylation of Glutamate dehydrogenase 1, mitochondrial (GLUD1). [32]
Bisphenol A DM2ZLD7 Investigative Bisphenol A increases the methylation of Glutamate dehydrogenase 1, mitochondrial (GLUD1). [47]
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18 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of Glutamate dehydrogenase 1, mitochondrial (GLUD1). [33]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of Glutamate dehydrogenase 1, mitochondrial (GLUD1). [34]
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of Glutamate dehydrogenase 1, mitochondrial (GLUD1). [35]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate decreases the expression of Glutamate dehydrogenase 1, mitochondrial (GLUD1). [36]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of Glutamate dehydrogenase 1, mitochondrial (GLUD1). [37]
Quercetin DM3NC4M Approved Quercetin decreases the expression of Glutamate dehydrogenase 1, mitochondrial (GLUD1). [38]
Arsenic trioxide DM61TA4 Approved Arsenic trioxide decreases the expression of Glutamate dehydrogenase 1, mitochondrial (GLUD1). [39]
Calcitriol DM8ZVJ7 Approved Calcitriol increases the expression of Glutamate dehydrogenase 1, mitochondrial (GLUD1). [40]
Testosterone DM7HUNW Approved Testosterone increases the expression of Glutamate dehydrogenase 1, mitochondrial (GLUD1). [40]
Azathioprine DMMZSXQ Approved Azathioprine decreases the expression of Glutamate dehydrogenase 1, mitochondrial (GLUD1). [41]
Capsaicin DMGMF6V Approved Capsaicin increases the expression of Glutamate dehydrogenase 1, mitochondrial (GLUD1). [42]
Propofol DMB4OLE Approved Propofol decreases the expression of Glutamate dehydrogenase 1, mitochondrial (GLUD1). [43]
Sevoflurane DMC9O43 Approved Sevoflurane increases the expression of Glutamate dehydrogenase 1, mitochondrial (GLUD1). [43]
Dihydrotestosterone DM3S8XC Phase 4 Dihydrotestosterone increases the expression of Glutamate dehydrogenase 1, mitochondrial (GLUD1). [45]
Epigallocatechin gallate DMCGWBJ Phase 3 Epigallocatechin gallate decreases the expression of Glutamate dehydrogenase 1, mitochondrial (GLUD1). [46]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the expression of Glutamate dehydrogenase 1, mitochondrial (GLUD1). [33]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 decreases the expression of Glutamate dehydrogenase 1, mitochondrial (GLUD1). [35]
Trichostatin A DM9C8NX Investigative Trichostatin A decreases the expression of Glutamate dehydrogenase 1, mitochondrial (GLUD1). [48]
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⏷ Show the Full List of 18 Drug(s)
1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT
Drug Name Drug ID Highest Status Interaction REF
Flucloxacillin DMNUWST Approved Flucloxacillin affects the binding of Glutamate dehydrogenase 1, mitochondrial (GLUD1). [44]
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References

1 A two-step approach improves the diagnosis of Clostridium difficile infection.J Microbiol Methods. 2017 Dec;143:17-19. doi: 10.1016/j.mimet.2017.09.015. Epub 2017 Sep 29.
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 Dominantly inherited hyperinsulinaemic hypoglycaemia.J Inherit Metab Dis. 2005;28(3):267-76. doi: 10.1007/s10545-005-7057-0.
4 Primary hyperoxaluria type 2: enzymology.J Nephrol. 1998 Mar-Apr;11 Suppl 1:29-31.
5 PDHA1 gene knockout in prostate cancer cells results in metabolic reprogramming towards greater glutamine dependence.Oncotarget. 2016 Aug 16;7(33):53837-53852. doi: 10.18632/oncotarget.10782.
6 Specific alteration in the expression of glial fibrillary acidic protein, glutamate dehydrogenase, and glutamine synthetase in rats with genetic absence epilepsy.Glia. 2000 Oct;32(1):15-24. doi: 10.1002/1098-1136(200010)32:1<15::aid-glia20>3.0.co;2-#.
7 -Ketoglutarate-Activated NF-B Signaling Promotes Compensatory Glucose Uptake and Brain Tumor Development.Mol Cell. 2019 Oct 3;76(1):148-162.e7. doi: 10.1016/j.molcel.2019.07.007. Epub 2019 Aug 22.
8 Glycerol-3-phosphate dehydrogenase activity in the red cells of patients with thalassemia.Blood. 1980 Apr;55(4):564-9.
9 Glutamate dehydrogenase (GLUD1) expression in breast cancer.Breast Cancer Res Treat. 2019 Feb;174(1):79-91. doi: 10.1007/s10549-018-5060-z. Epub 2018 Nov 23.
10 Urinary alpha-ketoglutarate is elevated in patients with hyperinsulinism-hyperammonemia syndrome.Clin Chim Acta. 2004 Mar;341(1-2):23-6. doi: 10.1016/j.cccn.2003.10.023.
11 Cerebellins are differentially expressed in selective subsets of neurons throughout the brain.J Comp Neurol. 2017 Oct 15;525(15):3286-3311. doi: 10.1002/cne.24278. Epub 2017 Jul 24.
12 Hyperinsulinism-hyperammonaemia syndrome: novel mutations in the GLUD1 gene and genotype-phenotype correlations.Eur J Endocrinol. 2009 Nov;161(5):731-5. doi: 10.1530/EJE-09-0615. Epub 2009 Aug 18.
13 Expression of enzymes regulating placental ammonia homeostasis in human fetal growth restricted pregnancies.Placenta. 2009 Jul;30(7):607-12. doi: 10.1016/j.placenta.2009.05.005. Epub 2009 Jun 4.
14 A novel high-resolution multilocus sequence typing of Giardia intestinalis Assemblage A isolates reveals zoonotic transmission, clonal outbreaks and recombination.Infect Genet Evol. 2018 Jun;60:7-16. doi: 10.1016/j.meegid.2018.02.012. Epub 2018 Feb 10.
15 Fifty Shades of -Ketoglutarate on Cellular Programming.Mol Cell. 2019 Oct 3;76(1):1-3. doi: 10.1016/j.molcel.2019.09.002.
16 Hominoid-specific enzyme GLUD2 promotes growth of IDH1R132H glioma.Proc Natl Acad Sci U S A. 2014 Sep 30;111(39):14217-22. doi: 10.1073/pnas.1409653111. Epub 2014 Sep 15.
17 Changes in glutamate-cycle enzyme mRNA levels in a rat model of hepatic encephalopathy.Metab Brain Dis. 1988 Jun;3(2):81-90. doi: 10.1007/BF01001011.
18 Congenital Hyperinsulinemic Hypoglycemia and Hyperammonemia due to Pathogenic Variants in GLUD1.Indian J Pediatr. 2019 Nov;86(11):1051-1053. doi: 10.1007/s12098-019-02980-x. Epub 2019 May 22.
19 LncRNA TUG1 sponges miR-145 to promote cancer progression and regulate glutamine metabolism via Sirt3/GDH axis.Oncotarget. 2017 Oct 19;8(69):113650-113661. doi: 10.18632/oncotarget.21922. eCollection 2017 Dec 26.
20 Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway.Nature. 2013 Apr 4;496(7443):101-5. doi: 10.1038/nature12040. Epub 2013 Mar 27.
21 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.
22 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.
23 Glutamate Dehydrogenase-Deficient Mice Display Schizophrenia-Like Behavioral Abnormalities and CA1-Specific Hippocampal Dysfunction.Schizophr Bull. 2019 Jan 1;45(1):127-137. doi: 10.1093/schbul/sby011.
24 Expression of glutamine synthetase and glutamate dehydrogenase in the latent phase and chronic phase in the kainate model of temporal lobe epilepsy.Glia. 2008 Jun;56(8):856-68. doi: 10.1002/glia.20659.
25 The PLAG1-GDH1 Axis Promotes Anoikis Resistance and Tumor Metastasis through CamKK2-AMPK Signaling in LKB1-Deficient Lung Cancer.Mol Cell. 2018 Jan 4;69(1):87-99.e7. doi: 10.1016/j.molcel.2017.11.025. Epub 2017 Dec 14.
26 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.
27 Hyperinsulinemic hypoglycemia: think of hyperinsulinism/hyperammonemia (HI/HA) syndrome caused by mutations in the GLUD1 gene.J Pediatr Endocrinol Metab. 2015 Jul;28(7-8):873-6. doi: 10.1515/jpem-2014-0441.
28 Neurological aspects of hyperinsulinism-hyperammonaemia syndrome.Dev Med Child Neurol. 2008 Dec;50(12):945-9. doi: 10.1111/j.1469-8749.2008.03114.x.
29 LncRNA XLOC_006390 promotes pancreatic carcinogenesis and glutamate metabolism by stabilizing c-Myc.Cancer Lett. 2020 Jan 28;469:419-428. doi: 10.1016/j.canlet.2019.11.021. Epub 2019 Nov 14.
30 The human GLUD2 glutamate dehydrogenase and its regulation in health and disease.Neurochem Int. 2011 Sep;59(4):495-509. doi: 10.1016/j.neuint.2011.03.015. Epub 2011 Mar 21.
31 Imbalance of excitatory/inhibitory synaptic protein expression in iPSC-derived neurons from FOXG1(+/-) patients and in foxg1(+/-) mice.Eur J Hum Genet. 2016 Jun;24(6):871-80. doi: 10.1038/ejhg.2015.216. Epub 2015 Oct 7.
32 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.
33 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.
34 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.
35 Gene expression changes associated with cytotoxicity identified using cDNA arrays. Funct Integr Genomics. 2000 Sep;1(2):114-26.
36 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
37 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.
38 Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
39 Proteomic and functional analyses reveal a dual molecular mechanism underlying arsenic-induced apoptosis in human multiple myeloma cells. J Proteome Res. 2009 Jun;8(6):3006-19.
40 Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
41 A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
42 A comparative proteomic analysis for capsaicin-induced apoptosis between human hepatocarcinoma (HepG2) and human neuroblastoma (SK-N-SH) cells. Proteomics. 2008 Nov;8(22):4748-67. doi: 10.1002/pmic.200800094.
43 Sevoflurane but not propofol enhances ovarian cancer cell biology through regulating cellular metabolic and signaling mechanisms. Cell Biol Toxicol. 2023 Aug;39(4):1395-1411. doi: 10.1007/s10565-022-09766-6. Epub 2022 Oct 8.
44 Identification of flucloxacillin-modified hepatocellular proteins: implications in flucloxacillin-induced liver injury. Toxicol Sci. 2023 Mar 20;192(1):106-116. doi: 10.1093/toxsci/kfad015.
45 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.
46 Epigallocatechin-3-gallate downregulates PDHA1 interfering the metabolic pathways in human herpesvirus 8 harboring primary effusion lymphoma cells. Toxicol In Vitro. 2020 Jun;65:104753. doi: 10.1016/j.tiv.2019.104753. Epub 2019 Dec 17.
47 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.
48 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.