Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0HUS40)

• DOT Name: Cysteine desulfurase (NFS1)
• Synonyms: EC 2.8.1.7
• Gene Name: NFS1
• Related Disease:
  Adenocarcinoma
  Combined oxidative phosphorylation deficiency 52
  Lung adenocarcinoma
  Lung neoplasm
  Obsolete severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency
• UniProt ID: NFS1_HUMAN
• PDB ID: 5KZ5; 5USR; 5WGB; 5WKP; 5WLW; 6NZU; 6UXE; 6W1D; 6WI2; 6WIH; 7RTK
• EC Number: 2.8.1.7
• Pfam ID: PF00266
• Sequence:
  MLLRAAWRRAAVAVTAAPGPKPAAPTRGLRLRVGDRAPQSAVPADTAAAPEVGPVLRPLY
  MDVQATTPLDPRVLDAMLPYLINYYGNPHSRTHAYGWESEAAMERARQQVASLIGADPRE
  IIFTSGATESNNIAIKGVARFYRSRKKHLITTQTEHKCVLDSCRSLEAEGFQVTYLPVQK
  SGIIDLKELEAAIQPDTSLVSVMTVNNEIGVKQPIAEIGRICSSRKVYFHTDAAQAVGKI
  PLDVNDMKIDLMSISGHKIYGPKGVGAIYIRRRPRVRVEALQSGGGQERGMRSGTVPTPL
  VVGLGAACEVAQQEMEYDHKRISKLSERLIQNIMKSLPDVVMNGDPKHHYPGCINLSFAY
  VEGESLLMALKDVALSSGSACTSASLEPSYVLRAIGTDEDLAHSSIRFGIGRFTTEEEVD
  YTVEKCIQHVKRLREMSPLWEMVQDGIDLKSIKWTQH
• Function: [Isoform Mitochondrial]: Cysteine desulfurase, of the core iron-sulfur cluster (ISC) assembly complex, that catalyzes the desulfuration of L-cysteine to L-alanine, as component of the cysteine desulfurase complex, leading to the formation of a cysteine persulfide intermediate at the active site cysteine residue and participates in the [2Fe-2S] clusters assembly on the scaffolding protein ISCU. The persulfide is then transferred on the flexible Cys loop from the catalytic site of NFS1 to the surface of NFS1. After the NFS1-linked persulfide sulfur is transferred to one of the conserved Cys residues of the scaffold, a reaction assisted by FXN. The core iron-sulfur cluster (ISC) assembly complex is involved in the de novo synthesis of a [2Fe-2S] cluster, the first step of the mitochondrial iron-sulfur protein biogenesis. This process is initiated by the cysteine desulfurase complex (NFS1:LYRM4:NDUFAB1) that produces persulfide which is delivered on the scaffold protein ISCU in a FXN-dependent manner. Then this complex is stabilized by FDX2 which provides reducing equivalents to accomplish the [2Fe-2S] cluster assembly. Finally, the [2Fe-2S] cluster is transferred from ISCU to chaperone proteins, including HSCB, HSPA9 and GLRX5; [Isoform Cytoplasmic]: May catalyze the desulfuration of L-cysteine to L-alanine as component of the cysteine desulfurase complex (NFS1:LYRM4), leading to the formation of a cysteine persulfide intermediate. Acts as a sulfur donor for MOCS3 by transferring the sulfur of the cysteine persulfide intermediate on MOCS3.
• Tissue Specificity: Predominantly expressed in heart and skeletal muscle. Also found in brain, liver and pancreas.
• KEGG Pathway:
  Thiamine metabolism (hsa00730)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
  Sulfur relay system (hsa04122)
• BioCyc Pathway: MetaCyc:HS01304-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[1]
Combined oxidative phosphorylation deficiency 52	DISQ3QRI	Strong	Autosomal recessive	[2]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[1]
Lung neoplasm	DISVARNB	Strong	Biomarker	[1]
Obsolete severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency	DISS963W	Supportive	Autosomal recessive	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Cysteine desulfurase (NFS1).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cysteine desulfurase (NFS1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cysteine desulfurase (NFS1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cysteine desulfurase (NFS1).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cysteine desulfurase (NFS1).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cysteine desulfurase (NFS1).	[9]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Cysteine desulfurase (NFS1).	[10]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Cysteine desulfurase (NFS1).	[11]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Cysteine desulfurase (NFS1).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cysteine desulfurase (NFS1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Cysteine desulfurase (NFS1).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Cysteine desulfurase (NFS1).	[13]

References

• [1] NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis.Nature. 2017 Nov 30;551(7682):639-643. doi: 10.1038/nature24637. Epub 2017 Nov 22.
• [2] RNA silencing of mitochondrial m-Nfs1 reduces Fe-S enzyme activity both in mitochondria and cytosol of mammalian cells. J Biol Chem. 2006 Sep 1;281(35):25398-406. doi: 10.1074/jbc.M602979200. Epub 2006 Jun 20.
• [3] Exome sequencing identifies NFS1 deficiency in a novel Fe-S cluster disease, infantile mitochondrial complex II/III deficiency. Mol Genet Genomic Med. 2014 Jan;2(1):73-80. doi: 10.1002/mgg3.46. Epub 2013 Nov 18.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [11] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [12] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [13] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [14] 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.
• [15] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.