Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3XMLYG)

• DOT Name: NADP-dependent malic enzyme, mitochondrial (ME3)
• Synonyms: NADP-ME; EC 1.1.1.40; Malic enzyme 3
• Gene Name: ME3
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Neoplasm
  Pancreatic cancer
  Acute myelogenous leukaemia
• UniProt ID: MAON_HUMAN
• PDB ID: 8E76; 8E78; 8E8O; 8EYN; 8EYO
• EC Number: 1.1.1.40
• Pfam ID: PF00390 ; PF03949
• Sequence:
  MGAALGTGTRLAPWPGRACGALPRWTPTAPAQGCHSKPGPARPVPLKKRGYDVTRNPHLN
  KGMAFTLEERLQLGIHGLIPPCFLSQDVQLLRIMRYYERQQSDLDKYIILMTLQDRNEKL
  FYRVLTSDVEKFMPIVYTPTVGLACQHYGLTFRRPRGLFITIHDKGHLATMLNSWPEDNI
  KAVVVTDGERILGLGDLGCYGMGIPVGKLALYTACGGVNPQQCLPVLLDVGTNNEELLRD
  PLYIGLKHQRVHGKAYDDLLDEFMQAVTDKFGINCLIQFEDFANANAFRLLNKYRNKYCM
  FNDDIQGTASVAVAGILAALRITKNKLSNHVFVFQGAGEAAMGIAHLLVMALEKEGVPKA
  EATRKIWMVDSKGLIVKGRSHLNHEKEMFAQDHPEVNSLEEVVRLVKPTAIIGVAAIAGA
  FTEQILRDMASFHERPIIFALSNPTSKAECTAEKCYRVTEGRGIFASGSPFKSVTLEDGK
  TFIPGQGNNAYVFPGVALGVIAGGIRHIPDEIFLLTAEQIAQEVSEQHLSQGRLYPPLST
  IRDVSLRIAIKVLDYAYKHNLASYYPEPKDKEAFVRSLVYTPDYDSFTLDSYTWPKEAMN
  VQTV
• Function: Catalyzes the oxidative decarboxylation of (S)-malate to pyruvate using NADP(+) as a cofactor. Can also reverse the decarboxylation reaction, but only with significantly lower efficiency.
• Tissue Specificity: Expressed predominantly in organs with a low-division rate.
• KEGG Pathway:
  Pyruvate metabolism (hsa00620)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  PPAR sig.ling pathway (hsa03320)
• Reactome Pathway: Citric acid cycle (TCA cycle) (R-HSA-71403)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Pancreatic cancer	DISJC981	Strong	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	NADP-dependent malic enzyme, mitochondrial (ME3) increases the Neutropenia ADR of Doxorubicin.	[21]

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 NADP-dependent malic enzyme, mitochondrial (ME3).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of NADP-dependent malic enzyme, mitochondrial (ME3).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of NADP-dependent malic enzyme, mitochondrial (ME3).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of NADP-dependent malic enzyme, mitochondrial (ME3).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of NADP-dependent malic enzyme, mitochondrial (ME3).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of NADP-dependent malic enzyme, mitochondrial (ME3).	[10]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of NADP-dependent malic enzyme, mitochondrial (ME3).	[8]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of NADP-dependent malic enzyme, mitochondrial (ME3).	[11]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of NADP-dependent malic enzyme, mitochondrial (ME3).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of NADP-dependent malic enzyme, mitochondrial (ME3).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of NADP-dependent malic enzyme, mitochondrial (ME3).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of NADP-dependent malic enzyme, mitochondrial (ME3).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of NADP-dependent malic enzyme, mitochondrial (ME3).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of NADP-dependent malic enzyme, mitochondrial (ME3).	[18]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of NADP-dependent malic enzyme, mitochondrial (ME3).	[19]
Manganese	DMKT129	Investigative	Manganese increases the expression of NADP-dependent malic enzyme, mitochondrial (ME3).	[20]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of NADP-dependent malic enzyme, mitochondrial (ME3).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of NADP-dependent malic enzyme, mitochondrial (ME3).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of NADP-dependent malic enzyme, mitochondrial (ME3).	[16]

References

• [1] Effects of ME3 on the proliferation, invasion and metastasis of pancreatic cancer cells through epithelial-mesenchymal transition.Neoplasma. 2019 Nov;66(6):896-907. doi: 10.4149/neo_2019_190119N59. Epub 2019 Oct 8.
• [2] Epigenetic silencing of triple negative breast cancer hallmarks by Withaferin A.Oncotarget. 2017 Jun 20;8(25):40434-40453. doi: 10.18632/oncotarget.17107.
• [3] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [6] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [7] 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.
• [8] 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.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [11] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [12] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [13] 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.
• [14] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [20] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.
• [21] Genome-wide association study of chemotherapeutic agent-induced severe neutropenia/leucopenia for patients in Biobank Japan. Cancer Sci. 2013 Aug;104(8):1074-82. doi: 10.1111/cas.12186. Epub 2013 Jun 10.