Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJF73BA)

• DOT Name: 5'(3')-deoxyribonucleotidase, mitochondrial (NT5M)
• Synonyms: 5',3'-nucleotidase, mitochondrial; EC 3.1.3.-; Deoxy-5'-nucleotidase 2; dNT-2
• Gene Name: NT5M
• Related Disease: Smith-Magenis syndrome
• UniProt ID: NT5M_HUMAN
• PDB ID: 1MH9; 1Q91; 1Q92; 1Z4I; 1Z4J; 1Z4K; 1Z4L; 1Z4M; 1Z4P; 1Z4Q; 2JAU; 2JAW; 4L6A; 4L6C; 4MUM; 4MWO; 4NFL; 4YIK; 6G22; 6G2L; 6G2M
• EC Number: 3.1.3.-
• Pfam ID: PF06941
• Sequence:
  MIRLGGWCARRLCSAAVPAGRRGAAGGLGLAGGRALRVLVDMDGVLADFEGGFLRKFRAR
  FPDQPFIALEDRRGFWVSEQYGRLRPGLSEKAISIWESKNFFFELEPLPGAVEAVKEMAS
  LQNTDVFICTSPIKMFKYCPYEKYAWVEKYFGPDFLEQIVLTRDKTVVSADLLIDDRPDI
  TGAEPTPSWEHVLFTACHNQHLQLQPPRRRLHSWADDWKAILDSKRPC
• Function: Dephosphorylates specifically the 5' and 2'(3')-phosphates of uracil and thymine deoxyribonucleotides, and so protects mitochondrial DNA replication from excess dTTP. Has only marginal activity towards dIMP and dGMP.
• Tissue Specificity: Highly expressed in heart, brain and skeletal muscle. Detected at very low levels in kidney and pancreas.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Pyrimidine metabolism (hsa00240)
  Nicoti.te and nicoti.mide metabolism (hsa00760)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
• Reactome Pathway: Pyrimidine catabolism (R-HSA-73621)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Smith-Magenis syndrome	DISG4G6X	Strong	Biomarker	[1]

3 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 5'(3')-deoxyribonucleotidase, mitochondrial (NT5M).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of 5'(3')-deoxyribonucleotidase, mitochondrial (NT5M).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of 5'(3')-deoxyribonucleotidase, mitochondrial (NT5M).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 5'(3')-deoxyribonucleotidase, mitochondrial (NT5M).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of 5'(3')-deoxyribonucleotidase, mitochondrial (NT5M).	[4]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of 5'(3')-deoxyribonucleotidase, mitochondrial (NT5M).	[6]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of 5'(3')-deoxyribonucleotidase, mitochondrial (NT5M).	[7]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of 5'(3')-deoxyribonucleotidase, mitochondrial (NT5M).	[8]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of 5'(3')-deoxyribonucleotidase, mitochondrial (NT5M).	[9]

References

• [1] A deoxyribonucleotidase in mitochondria: involvement in regulation of dNTP pools and possible link to genetic disease.Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8239-44. doi: 10.1073/pnas.97.15.8239.
• [2] 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.
• [3] 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.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] 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.
• [6] Expression profiling of nucleotide metabolism-related genes in human breast cancer cells after treatment with 5-fluorouracil. Cancer Invest. 2009 Jun;27(5):561-7.
• [7] 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.
• [8] Anti-proliferative and gene expression actions of resveratrol in breast cancer cells in vitro. Oncotarget. 2014 Dec 30;5(24):12891-907.
• [9] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [10] 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.