Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO4LL76)

• DOT Name: NAD-dependent malic enzyme, mitochondrial (ME2)
• Synonyms: NAD-ME; EC 1.1.1.38; Malic enzyme 2
• Gene Name: ME2
• Related Disease:
  Acute erythroid leukemia
  Advanced cancer
  Bipolar disorder
  Epilepsy
  Epilepsy, idiopathic generalized
  Juvenile myoclonic epilepsy
  leukaemia
  Leukemia
  Lung neoplasm
  Matthew-Wood syndrome
  Non-small-cell lung cancer
  Pancreatic cancer
  Psychotic disorder
  Schizophrenia
  Tourette syndrome
• UniProt ID: MAOM_HUMAN
• PDB ID: 1DO8; 1EFK; 1EFL; 1GZ3; 1GZ4; 1PJ2; 1PJ3; 1PJ4; 1PJL; 1QR6; 7BSJ; 7BSK; 7BSL; 7XDE; 7XDF; 7XDG
• EC Number: 1.1.1.38
• Pfam ID: PF00390 ; PF03949
• Sequence:
  MLSRLRVVSTTCTLACRHLHIKEKGKPLMLNPRTNKGMAFTLQERQMLGLQGLLPPKIET
  QDIQALRFHRNLKKMTSPLEKYIYIMGIQERNEKLFYRILQDDIESLMPIVYTPTVGLAC
  SQYGHIFRRPKGLFISISDRGHVRSIVDNWPENHVKAVVVTDGERILGLGDLGVYGMGIP
  VGKLCLYTACAGIRPDRCLPVCIDVGTDNIALLKDPFYMGLYQKRDRTQQYDDLIDEFMK
  AITDRYGRNTLIQFEDFGNHNAFRFLRKYREKYCTFNDDIQGTAAVALAGLLAAQKVISK
  PISEHKILFLGAGEAALGIANLIVMSMVENGLSEQEAQKKIWMFDKYGLLVKGRKAKIDS
  YQEPFTHSAPESIPDTFEDAVNILKPSTIIGVAGAGRLFTPDVIRAMASINERPVIFALS
  NPTAQAECTAEEAYTLTEGRCLFASGSPFGPVKLTDGRVFTPGQGNNVYIFPGVALAVIL
  CNTRHISDSVFLEAAKALTSQLTDEELAQGRLYPPLANIQEVSINIAIKVTEYLYANKMA
  FRYPEPEDKAKYVKERTWRSEYDSLLPDVYEWPESASSPPVITE
• Function: NAD-dependent mitochondrial malic enzyme that catalyzes the oxidative decarboxylation of malate to pyruvate.
• KEGG Pathway:
  Pyruvate metabolism (hsa00620)
  Carbon metabolism (hsa01200)
• Reactome Pathway: Citric acid cycle (TCA cycle) (R-HSA-71403)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute erythroid leukemia	DISZFC1O	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[3]
Epilepsy	DISBB28L	Strong	Biomarker	[4]
Epilepsy, idiopathic generalized	DISODZC9	Strong	Genetic Variation	[5]
Juvenile myoclonic epilepsy	DISYXV1N	Strong	Genetic Variation	[6]
leukaemia	DISS7D1V	Strong	Biomarker	[1]
Leukemia	DISNAKFL	Strong	Biomarker	[1]
Lung neoplasm	DISVARNB	Strong	Biomarker	[7]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[7]
Pancreatic cancer	DISJC981	Strong	Genetic Variation	[8]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[3]
Schizophrenia	DISSRV2N	Strong	Biomarker	[3]
Tourette syndrome	DISX9D54	No Known	Unknown	[9]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Josamycin	DMKJ8LB	Approved	NAD-dependent malic enzyme, mitochondrial (ME2) affects the response to substance of Josamycin.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of NAD-dependent malic enzyme, mitochondrial (ME2).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of NAD-dependent malic enzyme, mitochondrial (ME2).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of NAD-dependent malic enzyme, mitochondrial (ME2).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NAD-dependent malic enzyme, mitochondrial (ME2).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of NAD-dependent malic enzyme, mitochondrial (ME2).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NAD-dependent malic enzyme, mitochondrial (ME2).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of NAD-dependent malic enzyme, mitochondrial (ME2).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of NAD-dependent malic enzyme, mitochondrial (ME2).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of NAD-dependent malic enzyme, mitochondrial (ME2).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NAD-dependent malic enzyme, mitochondrial (ME2).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of NAD-dependent malic enzyme, mitochondrial (ME2).	[20]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of NAD-dependent malic enzyme, mitochondrial (ME2).	[21]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of NAD-dependent malic enzyme, mitochondrial (ME2).	[22]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of NAD-dependent malic enzyme, mitochondrial (ME2).	[23]

References

• [1] Induction of erythroid differentiation in human erythroleukemia cells by depletion of malic enzyme 2.PLoS One. 2010 Sep 2;5(9):e12520. doi: 10.1371/journal.pone.0012520.
• [2] Malic enzyme 2 as a potential therapeutic drug target for cancer.IUBMB Life. 2018 Nov;70(11):1076-1083. doi: 10.1002/iub.1930. Epub 2018 Aug 29.
• [3] Malic enzyme 2 and susceptibility to psychosis and mania.Psychiatry Res. 2007 Feb 28;150(1):1-11. doi: 10.1016/j.psychres.2006.06.001. Epub 2007 Jan 29.
• [4] A Pragmatic Test for Detecting Association between a Dichotomous Trait and the Genotypes of Affected Families, Controls and Independent Cases.Front Genet. 2017 May 9;8:49. doi: 10.3389/fgene.2017.00049. eCollection 2017.
• [5] Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy.Am J Hum Genet. 2005 Jan;76(1):139-46. doi: 10.1086/426735. Epub 2004 Nov 5.
• [6] Sacred disease secrets revealed: the genetics of human epilepsy.Hum Mol Genet. 2005 Oct 15;14 Spec No. 2:2491-2500.
• [7] Knockdown of malic enzyme 2 suppresses lung tumor growth, induces differentiation and impacts PI3K/AKT signaling.Sci Rep. 2014 Jun 24;4:5414. doi: 10.1038/srep05414.
• [8] Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer.Nature. 2017 Feb 2;542(7639):119-123. doi: 10.1038/nature21052. Epub 2017 Jan 18.
• [9] De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Neuron. 2017 May 3;94(3):486-499.e9. doi: 10.1016/j.neuron.2017.04.024.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [13] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [18] 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.
• [19] 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.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [21] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [22] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [23] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.
• [24] A genome-wide analysis of targets of macrolide antibiotics in mammalian cells. J Biol Chem. 2020 Feb 14;295(7):2057-2067. doi: 10.1074/jbc.RA119.010770. Epub 2020 Jan 8.