Details of Drug Off-Target (DOT)

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

• DOT Name: NAD(P) transhydrogenase, mitochondrial (NNT)
• Synonyms: EC 7.1.1.1; Nicotinamide nucleotide transhydrogenase; Pyridine nucleotide transhydrogenase
• Gene Name: NNT
• Related Disease:
  Glucocorticoid deficiency 4
  Familial glucocorticoid deficiency
• UniProt ID: NNTM_HUMAN
• PDB ID: 1DJL; 1PT9; 1U31
• EC Number: 7.1.1.1
• Pfam ID: PF01262 ; PF05222 ; PF02233 ; PF12769
• Sequence:
  MANLLKTVVTGCSCPLLSNLGSCKGLRVKKDFLRTFYTHQELWCKAPVKPGIPYKQLTVG
  VPKEIFQNEKRVALSPAGVQNLVKQGFNVVVESGAGEASKFSDDHYRVAGAQIQGAKEVL
  ASDLVVKVRAPMVNPTLGVHEADLLKTSGTLISFIYPAQNPELLNKLSQRKTTVLAMDQV
  PRVTIAQGYDALSSMANIAGYKAVVLAANHFGRFFTGQITAAGKVPPAKILIVGGGVAGL
  ASAGAAKSMGAIVRGFDTRAAALEQFKSLGAEPLEVDLKESGEGQGGYAKEMSKEFIEAE
  MKLFAQQCKEVDILISTALIPGKKAPVLFNKEMIESMKEGSVVVDLAAEAGGNFETTKPG
  ELYIHKGITHIGYTDLPSRMATQASTLYSNNITKLLKAISPDKDNFYFDVKDDFDFGTMG
  HVIRGTVVMKDGKVIFPAPTPKNIPQGAPVKQKTVAELEAEKAATITPFRKTMSTASAYT
  AGLTGILGLGIAAPNLAFSQMVTTFGLAGIVGYHTVWGVTPALHSPLMSVTNAISGLTAV
  GGLALMGGHLYPSTTSQGLAALAAFISSVNIAGGFLVTQRMLDMFKRPTDPPEYNYLYLL
  PAGTFVGGYLAALYSGYNIEQIMYLGSGLCCVGALAGLSTQGTARLGNALGMIGVAGGLA
  ATLGVLKPGPELLAQMSGAMALGGTIGLTIAKRIQISDLPQLVAAFHSLVGLAAVLTCIA
  EYIIEYPHFATDAAANLTKIVAYLGTYIGGVTFSGSLIAYGKLQGLLKSAPLLLPGRHLL
  NAGLLAASVGGIIPFMVDPSFTTGITCLGSVSALSAVMGVTLTAAIGGADMPVVITVLNS
  YSGWALCAEGFLLNNNLLTIVGALIGSSGAILSYIMCVAMNRSLANVILGGYGTTSTAGG
  KPMEISGTHTEINLDNAIDMIREANSIIITPGYGLCAAKAQYPIADLVKMLTEQGKKVRF
  GIHPVAGRMPGQLNVLLAEAGVPYDIVLEMDEINHDFPDTDLVLVIGANDTVNSAAQEDP
  NSIIAGMPVLEVWKSKQVIVMKRSLGVGYAAVDNPIFYKPNTAMLLGDAKKTCDALQAKV
  RESYQK
• Function: The transhydrogenation between NADH and NADP is coupled to respiration and ATP hydrolysis and functions as a proton pump across the membrane. May play a role in reactive oxygen species (ROS) detoxification in the adrenal gland.
• Tissue Specificity: Widely expressed with expression most readily detectable in adrenal, heart, kidney, thyroid and adipose tissues.
• KEGG Pathway:
  Nicoti.te and nicoti.mide metabolism (hsa00760)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Citric acid cycle (TCA cycle) (R-HSA-71403)
• BioCyc Pathway: MetaCyc:HS03639-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glucocorticoid deficiency 4	DISRLUI6	Definitive	Autosomal recessive	[1]
Familial glucocorticoid deficiency	DISG7TB4	Supportive	Autosomal recessive	[2]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
D-glucose	DMMG2TO	Investigative	NAD(P) transhydrogenase, mitochondrial (NNT) decreases the metabolism of D-glucose.	[24]

20 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 NAD(P) transhydrogenase, mitochondrial (NNT).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of NAD(P) transhydrogenase, mitochondrial (NNT).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NAD(P) transhydrogenase, mitochondrial (NNT).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of NAD(P) transhydrogenase, mitochondrial (NNT).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NAD(P) transhydrogenase, mitochondrial (NNT).	[7]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of NAD(P) transhydrogenase, mitochondrial (NNT).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NAD(P) transhydrogenase, mitochondrial (NNT).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of NAD(P) transhydrogenase, mitochondrial (NNT).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of NAD(P) transhydrogenase, mitochondrial (NNT).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of NAD(P) transhydrogenase, mitochondrial (NNT).	[13]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of NAD(P) transhydrogenase, mitochondrial (NNT).	[14]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of NAD(P) transhydrogenase, mitochondrial (NNT).	[15]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of NAD(P) transhydrogenase, mitochondrial (NNT).	[8]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of NAD(P) transhydrogenase, mitochondrial (NNT).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of NAD(P) transhydrogenase, mitochondrial (NNT).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of NAD(P) transhydrogenase, mitochondrial (NNT).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of NAD(P) transhydrogenase, mitochondrial (NNT).	[20]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of NAD(P) transhydrogenase, mitochondrial (NNT).	[21]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of NAD(P) transhydrogenase, mitochondrial (NNT).	[22]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of NAD(P) transhydrogenase, mitochondrial (NNT).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the methylation of NAD(P) transhydrogenase, mitochondrial (NNT).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of NAD(P) transhydrogenase, mitochondrial (NNT).	[17]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency. Nat Genet. 2012 May 27;44(7):740-2. doi: 10.1038/ng.2299.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] CRISPR-based DNA methylation editing of NNT rescues the cisplatin resistance of lung cancer cells by reducing autophagy. Arch Toxicol. 2023 Feb;97(2):441-456. doi: 10.1007/s00204-022-03404-0. Epub 2022 Nov 6.
• [9] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [10] 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.
• [11] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [12] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [13] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [14] 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.
• [15] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [16] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [17] 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.
• [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] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [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] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [22] Lipid Rafts Disruption Increases Ochratoxin A Cytotoxicity to Hepatocytes. J Biochem Mol Toxicol. 2016 Feb;30(2):71-9. doi: 10.1002/jbt.21738. Epub 2015 Aug 25.
• [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] Cofactor balance by nicotinamide nucleotide transhydrogenase (NNT) coordinates reductive carboxylation and glucose catabolism in the tricarboxylic acid (TCA) cycle. J Biol Chem. 2013 May 3;288(18):12967-77. doi: 10.1074/jbc.M112.396796. Epub 2013 Mar 15.