Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD5FS4Q)

• DOT Name: Glutamine-dependent NAD(+) synthetase (NADSYN1)
• Synonyms: EC 6.3.5.1; NAD(+) synthase ; NAD(+) synthetase
• Gene Name: NADSYN1
• Related Disease:
  Vertebral, cardiac, renal, and limb defects syndrome 3
  Congenital vertebral-cardiac-renal anomalies syndrome
• UniProt ID: NADE_HUMAN
• PDB ID: 6OFB
• EC Number: 6.3.5.1
• Pfam ID: PF00795 ; PF02540
• Sequence:
  MGRKVTVATCALNQWALDFEGNLQRILKSIEIAKNRGARYRLGPELEICGYGCWDHYYES
  DTLLHSFQVLAALVESPVTQDIICDVGMPVMHRNVRYNCRVIFLNRKILLIRPKMALANE
  GNYRELRWFTPWSRSRHTEEYFLPRMIQDLTKQETVPFGDAVLVTWDTCIGSEICEELWT
  PHSPHIDMGLDGVEIITNASGSHQVLRKANTRVDLVTMVTSKNGGIYLLANQKGCDGDRL
  YYDGCAMIAMNGSVFAQGSQFSLDDVEVLTATLDLEDVRSYRAEISSRNLAASRASPYPR
  VKVDFALSCHEDLLAPISEPIEWKYHSPEEEISLGPACWLWDFLRRSQQAGFLLPLSGGV
  DSAATACLIYSMCCQVCEAVRSGNEEVLADVRTIVNQISYTPQDPRDLCGRILTTCYMAS
  KNSSQETCTRARELAQQIGSHHISLNIDPAVKAVMGIFSLVTGKSPLFAAHGGSSRENLA
  LQNVQARIRMVLAYLFAQLSLWSRGVHGGLLVLGSANVDESLLGYLTKYDCSSADINPIG
  GISKTDLRAFVQFCIQRFQLPALQSILLAPATAELEPLADGQVSQTDEEDMGMTYAELSV
  YGKLRKVAKMGPYSMFCKLLGMWRHICTPRQVADKVKRFFSKYSMNRHKMTTLTPAYHAE
  NYSPEDNRFDLRPFLYNTSWPWQFRCIENQVLQLERAEPQSLDGVD
• Function: Catalyzes the final step of the nicotinamide adenine dinucleotide (NAD) de novo synthesis pathway, the ATP-dependent amidation of deamido-NAD using L-glutamine as a nitrogen source.
• KEGG Pathway:
  Nicoti.te and nicoti.mide metabolism (hsa00760)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Nicotinate metabolism (R-HSA-196807)
• BioCyc Pathway: MetaCyc:HS10587-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
Vertebral, cardiac, renal, and limb defects syndrome 3	DIS4X57K	Moderate	Autosomal recessive	[1]
Congenital vertebral-cardiac-renal anomalies syndrome	DISR2YKP	Supportive	Autosomal recessive	[2]

13 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 Glutamine-dependent NAD(+) synthetase (NADSYN1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glutamine-dependent NAD(+) synthetase (NADSYN1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Glutamine-dependent NAD(+) synthetase (NADSYN1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Glutamine-dependent NAD(+) synthetase (NADSYN1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Glutamine-dependent NAD(+) synthetase (NADSYN1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glutamine-dependent NAD(+) synthetase (NADSYN1).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Glutamine-dependent NAD(+) synthetase (NADSYN1).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Glutamine-dependent NAD(+) synthetase (NADSYN1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Glutamine-dependent NAD(+) synthetase (NADSYN1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Glutamine-dependent NAD(+) synthetase (NADSYN1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Glutamine-dependent NAD(+) synthetase (NADSYN1).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Glutamine-dependent NAD(+) synthetase (NADSYN1).	[14]
OXYRESVERATROL	DMN7S4L	Investigative	OXYRESVERATROL increases the expression of Glutamine-dependent NAD(+) synthetase (NADSYN1).	[15]

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] Bi-allelic Mutations in NADSYN1 Cause Multiple Organ Defects and Expand the Genotypic Spectrum of Congenital NAD Deficiency Disorders. Am J Hum Genet. 2020 Jan 2;106(1):129-136. doi: 10.1016/j.ajhg.2019.12.006. Epub 2019 Dec 26.
• [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] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] 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.
• [9] 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.
• [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] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [12] 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.
• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Oxyresveratrol stimulates mucin production in an NAD+-dependent manner in human intestinal goblet cells. Food Chem Toxicol. 2018 Aug;118:880-888.