Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1I8GDE)

• DOT Name: NAD kinase 2, mitochondrial (NADK2)
• Synonyms: EC 2.7.1.23; Mitochondrial NAD kinase; NAD kinase domain-containing protein 1, mitochondrial
• Gene Name: NADK2
• Related Disease:
  Fatty liver disease
  Non-alcoholic fatty liver disease
  Progressive encephalopathy with leukodystrophy due to DECR deficiency
• UniProt ID: NAKD2_HUMAN
• PDB ID: 7N29; 7R4J; 7R4K; 7R4L; 7R4M
• EC Number: 2.7.1.23
• Pfam ID: PF01513
• Sequence:
  MTCYRGFLLGSCCRVAGGRAAALRGPGAGGPAARPRLGGDGGGRRHLGQGQPRELAGCGS
  RADGGFRPSRVVVVAKTTRYEFEQQRYRYAELSEEDLKQLLALKGSSYSGLLERHHIHTK
  NVEHIIDSLRNEGIEVRLVKRREYDEETVRWADAVIAAGGDGTMLLAASKVLDRLKPVIG
  VNTDPERSEGHLCLPVRYTHSFPEALQKFYRGEFRWLWRQRIRLYLEGTGINPVPVDLHE
  QQLSLNQHNRALNIERAHDERSEASGPQLLPVRALNEVFIGESLSSRASYYEISVDDGPW
  EKQKSSGLNLCTGTGSKAWSFNINRVATQAVEDVLNIAKRQGNLSLPLNRELVEKVTNEY
  NESLLYSPEEPKILFSIREPIANRVFSSSRQRCFSSKVCVRSRCWDACMVVDGGTSFEFN
  DGAIASMMINKEDELRTVLLEQ
• Function: Mitochondrial NAD(+) kinase that phosphorylates NAD(+) to yield NADP(+). Can use both ATP or inorganic polyphosphate as the phosphoryl donor. Also has weak NADH kinase activity in vitro; however NADH kinase activity is much weaker than the NAD(+) kinase activity and may not be relevant in vivo.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Nicoti.te and nicoti.mide metabolism (hsa00760)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Nicotinate metabolism (R-HSA-196807)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fatty liver disease	DIS485QZ	Strong	Genetic Variation	[1]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[1]
Progressive encephalopathy with leukodystrophy due to DECR deficiency	DISOCW9E	Strong	Autosomal recessive	[2]

6 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 NAD kinase 2, mitochondrial (NADK2).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of NAD kinase 2, mitochondrial (NADK2).	[10]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of NAD kinase 2, mitochondrial (NADK2).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of NAD kinase 2, mitochondrial (NADK2).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of NAD kinase 2, mitochondrial (NADK2).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of NAD kinase 2, mitochondrial (NADK2).	[12]

14 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 NAD kinase 2, mitochondrial (NADK2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of NAD kinase 2, mitochondrial (NADK2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NAD kinase 2, mitochondrial (NADK2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NAD kinase 2, mitochondrial (NADK2).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of NAD kinase 2, mitochondrial (NADK2).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NAD kinase 2, mitochondrial (NADK2).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of NAD kinase 2, mitochondrial (NADK2).	[11]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of NAD kinase 2, mitochondrial (NADK2).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of NAD kinase 2, mitochondrial (NADK2).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of NAD kinase 2, mitochondrial (NADK2).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of NAD kinase 2, mitochondrial (NADK2).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of NAD kinase 2, mitochondrial (NADK2).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of NAD kinase 2, mitochondrial (NADK2).	[19]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of NAD kinase 2, mitochondrial (NADK2).	[8]

References

• [1] Deficiency of the Mitochondrial NAD Kinase Causes Stress-Induced Hepatic Steatosis in Mice.Gastroenterology. 2018 Jan;154(1):224-237. doi: 10.1053/j.gastro.2017.09.010. Epub 2017 Sep 18.
• [2] Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia. Hum Mol Genet. 2014 Sep 15;23(18):5009-16. doi: 10.1093/hmg/ddu218. Epub 2014 May 8.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.