Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJEO4E8)

• DOT Name: Malate dehydrogenase, cytoplasmic (MDH1)
• Synonyms: EC 1.1.1.37; Aromatic alpha-keto acid reductase; KAR; EC 1.1.1.96; Cytosolic malate dehydrogenase
• Gene Name: MDH1
• Related Disease:
  Pancreatic ductal carcinoma
  Alzheimer disease
  Creutzfeldt Jacob disease
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1A
  Fatal familial insomnia
  Gerstmann-Straussler-Scheinker syndrome
  High blood pressure
  Matthew-Wood syndrome
  Metabolic disorder
  Neoplasm
  Non-small-cell lung cancer
  Pancreatic cancer
  Retinitis pigmentosa
  Advanced cancer
  Schizophrenia
  Adult respiratory distress syndrome
  Amyotrophic lateral sclerosis
  Developmental and epileptic encephalopathy, 88
• UniProt ID: MDHC_HUMAN
• PDB ID: 7RM9; 7RRL
• EC Number: 1.1.1.37; 1.1.1.96
• Pfam ID: PF02866 ; PF00056
• Sequence:
  MSEPIRVLVTGAAGQIAYSLLYSIGNGSVFGKDQPIILVLLDITPMMGVLDGVLMELQDC
  ALPLLKDVIATDKEDVAFKDLDVAILVGSMPRREGMERKDLLKANVKIFKSQGAALDKYA
  KKSVKVIVVGNPANTNCLTASKSAPSIPKENFSCLTRLDHNRAKAQIALKLGVTANDVKN
  VIIWGNHSSTQYPDVNHAKVKLQGKEVGVYEALKDDSWLKGEFVTTVQQRGAAVIKARKL
  SSAMSAAKAICDHVRDIWFGTPEGEFVSMGVISDGNSYGVPDDLLYSFPVVIKNKTWKFV
  EGLPINDFSREKMDLTAKELTEEKESAFEFLSSA
• Function: Catalyzes the reduction of aromatic alpha-keto acids in the presence of NADH. Plays essential roles in the malate-aspartate shuttle and the tricarboxylic acid cycle, important in mitochondrial NADH supply for oxidative phosphorylation. Catalyzes the reduction of 2-oxoglutarate to 2-hydroxyglutarate, leading to elevated reactive oxygen species (ROS).
• KEGG Pathway:
  Citrate cycle (TCA cycle) (hsa00020)
  Cysteine and methionine metabolism (hsa00270)
  Pyruvate metabolism (hsa00620)
  Glyoxylate and dicarboxylate metabolism (hsa00630)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  Proximal tubule bicarbo.te reclamation (hsa04964)
• Reactome Pathway: Gluconeogenesis (R-HSA-70263)
• BioCyc Pathway: MetaCyc:HS00361-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pancreatic ductal carcinoma	DIS26F9Q	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[2]
Creutzfeldt Jacob disease	DISCB6RX	Strong	Biomarker	[3]
Dilated cardiomyopathy	DISX608J	Strong	Altered Expression	[4]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[4]
Fatal familial insomnia	DIS1FL1J	Strong	Genetic Variation	[3]
Gerstmann-Straussler-Scheinker syndrome	DISIO6KC	Strong	Genetic Variation	[3]
High blood pressure	DISY2OHH	Strong	Biomarker	[5]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[1]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[8]
Pancreatic cancer	DISJC981	Strong	Posttranslational Modification	[9]
Retinitis pigmentosa	DISCGPY8	Strong	Biomarker	[10]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[11]
Schizophrenia	DISSRV2N	moderate	Altered Expression	[12]
Adult respiratory distress syndrome	DISIJV47	Limited	Biomarker	[13]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Genetic Variation	[14]
Developmental and epileptic encephalopathy, 88	DISY22AX	Limited	Unknown	[15]

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 Malate dehydrogenase, cytoplasmic (MDH1).	[16]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Malate dehydrogenase, cytoplasmic (MDH1).	[33]

23 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 Malate dehydrogenase, cytoplasmic (MDH1).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Malate dehydrogenase, cytoplasmic (MDH1).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Malate dehydrogenase, cytoplasmic (MDH1).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Malate dehydrogenase, cytoplasmic (MDH1).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Malate dehydrogenase, cytoplasmic (MDH1).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Malate dehydrogenase, cytoplasmic (MDH1).	[22]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Malate dehydrogenase, cytoplasmic (MDH1).	[23]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Malate dehydrogenase, cytoplasmic (MDH1).	[24]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Malate dehydrogenase, cytoplasmic (MDH1).	[25]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Malate dehydrogenase, cytoplasmic (MDH1).	[26]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Malate dehydrogenase, cytoplasmic (MDH1).	[27]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Malate dehydrogenase, cytoplasmic (MDH1).	[28]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Malate dehydrogenase, cytoplasmic (MDH1).	[29]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Malate dehydrogenase, cytoplasmic (MDH1).	[30]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Malate dehydrogenase, cytoplasmic (MDH1).	[28]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Malate dehydrogenase, cytoplasmic (MDH1).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Malate dehydrogenase, cytoplasmic (MDH1).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Malate dehydrogenase, cytoplasmic (MDH1).	[34]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Malate dehydrogenase, cytoplasmic (MDH1).	[35]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Malate dehydrogenase, cytoplasmic (MDH1).	[36]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Malate dehydrogenase, cytoplasmic (MDH1).	[37]
Oxalacetic acid	DMPZSV1	Investigative	Oxalacetic acid increases the expression of Malate dehydrogenase, cytoplasmic (MDH1).	[37]
malic acid	DMU3O5H	Investigative	malic acid increases the expression of Malate dehydrogenase, cytoplasmic (MDH1).	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Dihydroartemisinin	DMBXVMZ	Approved	Dihydroartemisinin affects the binding of Malate dehydrogenase, cytoplasmic (MDH1).	[31]

References

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• [3] Evaluation of Human Cerebrospinal Fluid Malate Dehydrogenase 1 as a Marker in Genetic Prion Disease Patients.Biomolecules. 2019 Nov 28;9(12):800. doi: 10.3390/biom9120800.
• [4] Developmental regulation and cellular distribution of human cytosolic malate dehydrogenase (MDH1).J Cell Biochem. 2005 Mar 1;94(4):763-73. doi: 10.1002/jcb.20343.
• [5] A custom rat and baboon hypertension gene array to compare experimental models.Exp Biol Med (Maywood). 2012 Jan;237(1):99-110. doi: 10.1258/ebm.2011.011188. Epub 2012 Jan 6.
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• [7] Cytosolic malate dehydrogenase activity helps support glycolysis in actively proliferating cells and cancer.Oncogene. 2017 Jul 6;36(27):3915-3924. doi: 10.1038/onc.2017.36. Epub 2017 Mar 6.
• [8] miR-126-5p targets Malate Dehydrogenase 1 in non-small cell lung carcinomas.Biochem Biophys Res Commun. 2018 May 5;499(2):314-320. doi: 10.1016/j.bbrc.2018.03.154. Epub 2018 Mar 26.
• [9] Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer.Mol Cell. 2016 Nov 17;64(4):673-687. doi: 10.1016/j.molcel.2016.09.028. Epub 2016 Nov 10.
• [10] Ultra high throughput sequencing excludes MDH1 as candidate gene for RP28-linked retinitis pigmentosa.Mol Vis. 2009 Dec 8;15:2627-33.
• [11] Consequences of blunting the mevalonate pathway in cancer identified by a pluri-omics approach.Cell Death Dis. 2018 Jul 3;9(7):745. doi: 10.1038/s41419-018-0761-0.
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• [14] Gain of interaction of ALS-linked G93A superoxide dismutase with cytosolic malate dehydrogenase.Neurobiol Dis. 2008 Oct;32(1):133-41. doi: 10.1016/j.nbd.2008.06.010. Epub 2008 Jul 3.
• [15] Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples. Nat Genet. 2017 Apr;49(4):504-510. doi: 10.1038/ng.3789. Epub 2017 Feb 13.
• [16] 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.
• [17] 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.
• [18] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [19] 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.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [22] 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.
• [23] Quantitative proteomic analysis of HepG2 cells treated with quercetin suggests IQGAP1 involved in quercetin-induced regulation of cell proliferation and migration. OMICS. 2009 Apr;13(2):93-103. doi: 10.1089/omi.2008.0075.
• [24] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [25] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [26] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [27] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [28] 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.
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• [30] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [31] Untargeted Proteomics and Systems-Based Mechanistic Investigation of Artesunate in Human Bronchial Epithelial Cells. Chem Res Toxicol. 2015 Oct 19;28(10):1903-13. doi: 10.1021/acs.chemrestox.5b00105. Epub 2015 Sep 21.
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• [33] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [34] 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.
• [35] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [36] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [37] Oxaloacetate enhances neuronal cell bioenergetic fluxes and infrastructure. J Neurochem. 2016 Apr;137(1):76-87. doi: 10.1111/jnc.13545. Epub 2016 Mar 11.