Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKEA582)

• DOT Name: NADPH-dependent diflavin oxidoreductase 1 (NDOR1)
• Synonyms: EC 1.18.1.-; NADPH-dependent FMN and FAD-containing oxidoreductase; Novel reductase 1
• Gene Name: NDOR1
• Related Disease: Schizophrenia
• UniProt ID: NDOR1_HUMAN
• PDB ID: 4H2D
• EC Number: 1.18.1.-
• Pfam ID: PF00667 ; PF00258 ; PF00175
• Sequence:
  MPSPQLLVLFGSQTGTAQDVSERLGREARRRRLGCRVQALDSYPVVNLINEPLVIFVCAT
  TGQGDPPDNMKNFWRFIFRKNLPSTALCQMDFAVLGLGDSSYAKFNFVAKKLHRRLLQLG
  GSALLPVCLGDDQHELGPDAAVDPWLRDLWDRVLGLYPPPPGLTEIPPGVPLPSKFTLLF
  LQEAPSTGSEGQRVAHPGSQEPPSESKPFLAPMISNQRVTGPSHFQDVRLIEFDILGSGI
  SFAAGDVVLIQPSNSAAHVQRFCQVLGLDPDQLFMLQPREPDVSSPTRLPQPCSMRHLVS
  HYLDIASVPRRSFFELLACLSLHELEREKLLEFSSAQGQEELFEYCNRPRRTILEVLCDF
  PHTAAAIPPDYLLDLIPVIRPRAFSIASSLLTHPSRLQILVAVVQFQTRLKEPRRGLCSS
  WLASLDPGQGPVRVPLWVRPGSLAFPETPDTPVIMVGPGTGVAPFRAAIQERVAQGQTGN
  FLFFGCRWRDQDFYWEAEWQELEKRDCLTLIPAFSREQEQKVYVQHRLRELGSLVWELLD
  RQGAYFYLAGNAKSMPADVSEALMSIFQEEGGLCSPDAAAYLARLQQTRRFQTETWA
• Function: NADPH-dependent reductase which is a central component of the cytosolic iron-sulfur (Fe-S) protein assembly (CIA) machinery. Transfers electrons from NADPH via its FAD and FMN prosthetic groups to the [2Fe-2S] cluster of CIAPIN1, another key component of the CIA machinery. In turn, this reduced cluster provides electrons for assembly of cytosolic iron-sulfur cluster proteins. It can also reduce the [2Fe-2S] cluster of CISD1 and activate this protein implicated in Fe/S cluster repair. In vitro can fully activate methionine synthase/MTR in the presence of soluble cytochrome b5/CYB5A.
• Tissue Specificity: Low expression in brain, heart, kidney, pancreas, prostate and skeletal muscle. Highest levels in the placenta. Expressed in cancer cell lines including promyelocytic leukemia, HeLaS3, chronic myelagenous leukemia, lymphoblastic leukemia, Burkitt's lymphoma, colorectal adenocarcinoma, lung carcinoma, and melanoma G-361.
• Reactome Pathway: Cytosolic iron-sulfur cluster assembly (R-HSA-2564830)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Schizophrenia	DISSRV2N	Strong	Altered Expression	[1]

2 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 NADPH-dependent diflavin oxidoreductase 1 (NDOR1).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of NADPH-dependent diflavin oxidoreductase 1 (NDOR1).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of NADPH-dependent diflavin oxidoreductase 1 (NDOR1).	[3]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of NADPH-dependent diflavin oxidoreductase 1 (NDOR1).	[4]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of NADPH-dependent diflavin oxidoreductase 1 (NDOR1).	[6]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of NADPH-dependent diflavin oxidoreductase 1 (NDOR1).	[7]

References

• [1] A quantitative review of the postmortem evidence for decreased cortical N-methyl-D-aspartate receptor expression levels in schizophrenia: How can we link molecular abnormalities to mismatch negativity deficits?.Biol Psychol. 2016 Apr;116:57-67. doi: 10.1016/j.biopsycho.2015.10.013. Epub 2015 Nov 10.
• [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] 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.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.