Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV232Y7)

• DOT Name: Glycerol-3-phosphate dehydrogenase, mitochondrial (GPD2)
• Synonyms: GPD-M; GPDH-M; EC 1.1.5.3; mitohondrial glycerophosphate dehydrogenase gene; mGDH; mtGPD
• Gene Name: GPD2
• Related Disease:
  Advanced cancer
  Citrin deficiency
  Citrullinemia type II
  Esophageal squamous cell carcinoma
  Glioma
  Insulinoma
  Intrahepatic cholestasis
  Language disorder
  Motion sickness
  Neonatal intrahepatic cholestasis due to citrin deficiency
  Neoplasm
  Osteoporosis
  Prostate neoplasm
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Intellectual disability
  Methylmalonic acidemia
  Myopia
  Obsolete diabetes mellitus, noninsulin-dependent
• UniProt ID: GPDM_HUMAN
• EC Number: 1.1.5.3
• Pfam ID: PF01266 ; PF16901 ; PF13499
• Sequence:
  MAFQKAVKGTILVGGGALATVLGLSQFAHYRRKQMNLAYVKAADCISEPVNREPPSREAQ
  LLTLQNTSEFDILVIGGGATGSGCALDAVTRGLKTALVERDDFSSGTSSRSTKLIHGGVR
  YLQKAIMKLDIEQYRMVKEALHERANLLEIAPHLSAPLPIMLPVYKWWQLPYYWVGIKLY
  DLVAGSNCLKSSYVLSKSRALEHFPMLQKDKLVGAIVYYDGQHNDARMNLAIALTAARYG
  AATANYMEVVSLLKKTDPQTGKVRVSGARCKDVLTGQEFDVRAKCVINATGPFTDSVRKM
  DDKDAAAICQPSAGVHIVMPGYYSPESMGLLDPATSDGRVIFFLPWQKMTIAGTTDTPTD
  VTHHPIPSEEDINFILNEVRNYLSCDVEVRRGDVLAAWSGIRPLVTDPKSADTQSISRNH
  VVDISESGLITIAGGKWTTYRSMAEDTINAAVKTHNLKAGPSRTVGLFLQGGKDWSPTLY
  IRLVQDYGLESEVAQHLAATYGDKAFEVAKMASVTGKRWPIVGVRLVSEFPYIEAEVKYG
  IKEYACTAVDMISRRTRLAFLNVQAAEEALPRIVELMGRELNWDDYKKQEQLETARKFLY
  YEMGYKSRSEQLTDRSEISLLPSDIDRYKKRFHKFDADQKGFITIVDVQRVLESINVQMD
  ENTLHEILNEVDLNKNGQVELNEFLQLMSAIQKGRVSGSRLAILMKTAEENLDRRVPIPV
  DRSCGGL
• Function: Calcium-responsive mitochondrial glycerol-3-phosphate dehydrogenase which seems to be a key component of the pancreatic beta-cell glucose-sensing device.
• KEGG Pathway: Glycerophospholipid metabolism (hsa00564)
• Reactome Pathway:
  Triglyceride catabolism (R-HSA-163560)
  Synthesis of PA (R-HSA-1483166)
• BioCyc Pathway: MetaCyc:HS03841-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Citrin deficiency	DISIJZ2R	Strong	Biomarker	[2]
Citrullinemia type II	DIS2UURN	Strong	Biomarker	[2]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Genetic Variation	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[4]
Insulinoma	DISIU1JS	Strong	Biomarker	[5]
Intrahepatic cholestasis	DISHITDZ	Strong	Biomarker	[2]
Language disorder	DISTLKP7	Strong	Genetic Variation	[6]
Motion sickness	DISZ2WZW	Strong	Genetic Variation	[7]
Neonatal intrahepatic cholestasis due to citrin deficiency	DIS8XETO	Strong	Genetic Variation	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Osteoporosis	DISF2JE0	Strong	Biomarker	[9]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[10]
Thyroid cancer	DIS3VLDH	Disputed	Biomarker	[8]
Thyroid gland carcinoma	DISMNGZ0	Disputed	Biomarker	[8]
Thyroid tumor	DISLVKMD	Disputed	Biomarker	[8]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[11]
Methylmalonic acidemia	DISHY8VB	Limited	Biomarker	[12]
Myopia	DISK5S60	Limited	Genetic Variation	[13]
Obsolete diabetes mellitus, noninsulin-dependent	DISS46MZ	No Known	Autosomal dominant	[14]

2 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 Glycerol-3-phosphate dehydrogenase, mitochondrial (GPD2).	[15]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Glycerol-3-phosphate dehydrogenase, mitochondrial (GPD2).	[18]

11 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 Glycerol-3-phosphate dehydrogenase, mitochondrial (GPD2).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glycerol-3-phosphate dehydrogenase, mitochondrial (GPD2).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Glycerol-3-phosphate dehydrogenase, mitochondrial (GPD2).	[19]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Glycerol-3-phosphate dehydrogenase, mitochondrial (GPD2).	[20]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Glycerol-3-phosphate dehydrogenase, mitochondrial (GPD2).	[21]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Glycerol-3-phosphate dehydrogenase, mitochondrial (GPD2).	[22]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Glycerol-3-phosphate dehydrogenase, mitochondrial (GPD2).	[23]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Glycerol-3-phosphate dehydrogenase, mitochondrial (GPD2).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Glycerol-3-phosphate dehydrogenase, mitochondrial (GPD2).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Glycerol-3-phosphate dehydrogenase, mitochondrial (GPD2).	[27]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Glycerol-3-phosphate dehydrogenase, mitochondrial (GPD2).	[28]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Glycerol-3-phosphate dehydrogenase, mitochondrial (GPD2).	[25]

References

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• [2] Effects of supplementation on food intake, body weight and hepatic metabolites in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double-knockout mouse model of human citrin deficiency.Mol Genet Metab. 2012 Nov;107(3):322-9. doi: 10.1016/j.ymgme.2012.07.021. Epub 2012 Aug 2.
• [3] A Novel Clinical Six-Flavoprotein-Gene Signature Predicts Prognosis in Esophageal Squamous Cell Carcinoma.Biomed Res Int. 2019 Oct 30;2019:3869825. doi: 10.1155/2019/3869825. eCollection 2019.
• [4] 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.
• [5] Molecular cloning of human mitochondrial glycerophosphate dehydrogenase gene: genomic structure, chromosomal localization, and existence of a pseudogene.Biochem Biophys Res Commun. 1996 Jun 25;223(3):481-6. doi: 10.1006/bbrc.1996.0920.
• [6] Haploinsufficiency of NR4A2 is associated with a neurodevelopmental phenotype with prominent language impairment.Am J Med Genet A. 2017 Aug;173(8):2231-2234. doi: 10.1002/ajmg.a.38288. Epub 2017 May 24.
• [7] Genetic variants associated with motion sickness point to roles for inner ear development, neurological processes and glucose homeostasis.Hum Mol Genet. 2015 May 1;24(9):2700-8. doi: 10.1093/hmg/ddv028. Epub 2015 Jan 26.
• [8] Metformin Targets Mitochondrial Glycerophosphate Dehydrogenase to Control Rate of Oxidative Phosphorylation and Growth of Thyroid Cancer In Vitro and In Vivo.Clin Cancer Res. 2018 Aug 15;24(16):4030-4043. doi: 10.1158/1078-0432.CCR-17-3167. Epub 2018 Apr 24.
• [9] Proteomic analysis of circulating monocytes in Chinese premenopausal females with extremely discordant bone mineral density.Proteomics. 2008 Oct;8(20):4259-72. doi: 10.1002/pmic.200700480.
• [10] Increased expression of mitochondrial glycerophosphate dehydrogenase and antioxidant enzymes in prostate cancer cell lines/cancer.Free Radic Res. 2007 Oct;41(10):1116-24. doi: 10.1080/10715760701579314.
• [11] Intellectual disability and hemizygous GPD2 mutation.Am J Med Genet A. 2013 May;161A(5):1044-50. doi: 10.1002/ajmg.a.35873. Epub 2013 Mar 29.
• [12] Quantitative analysis of mitochondrial protein expression in methylmalonic acidemia by two-dimensional difference gel electrophoresis.J Proteome Res. 2006 Jul;5(7):1602-10. doi: 10.1021/pr050481r.
• [13] Detection and interpretation of shared genetic influences on 42 human traits.Nat Genet. 2016 Jul;48(7):709-17. doi: 10.1038/ng.3570. Epub 2016 May 16.
• [14] Mutation in the calcium-binding domain of the mitochondrial glycerophosphate dehydrogenase gene in a family of diabetic subjects. Biochem Biophys Res Commun. 1997 Feb 24;231(3):570-2. doi: 10.1006/bbrc.1997.6147.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [20] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [21] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] Effects of troglitazone on cellular differentiation, insulin signaling, and glucose metabolism in cultured human skeletal muscle cells. Biochem Biophys Res Commun. 2001 Jan 26;280(3):664-74. doi: 10.1006/bbrc.2000.4216.
• [24] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [25] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [26] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [27] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [28] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.