Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK6JCKL)

• DOT Name: LYR motif-containing protein 4 (LYRM4)
• Gene Name: LYRM4
• Related Disease:
  Narcolepsy
  Friedreich ataxia 1
  Ulcerative colitis
  Schizophrenia
  Obsolete severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency
  Combined oxidative phosphorylation deficiency 19
  Crohn disease
• UniProt ID: LYRM4_HUMAN
• PDB ID: 5USR; 5WGB; 5WKP; 5WLW; 6NZU; 6ODD; 6UXE; 6W1D; 6WI2; 6WIH; 7RTK
• Pfam ID: PF05347
• Sequence:
  MAASSRAQVLSLYRAMLRESKRFSAYNYRTYAVRRIRDAFRENKNVKDPVEIQTLVNKAK
  RDLGVIRRQVHIGQLYSTDKLIIENRDMPRT
• Function: Stabilizing factor, of the core iron-sulfur cluster (ISC) assembly complex, that regulates, in association with NDUFAB1, the stability and the cysteine desulfurase activity of NFS1 and participates in the [2Fe-2S] clusters assembly on the scaffolding protein ISCU. 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. May also participates in the iron-sulfur protein biogenesis in the cytoplasm through its interaction with the cytoplasmic form of NFS1.
• Tissue Specificity: Reduced mRNA levels in Friedreich ataxia patients.
• Reactome Pathway: Mitochondrial iron-sulfur cluster biogenesis (R-HSA-1362409)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Narcolepsy	DISLCNLI	Definitive	Genetic Variation	[1]
Friedreich ataxia 1	DIS285GE	Strong	Genetic Variation	[2]
Ulcerative colitis	DIS8K27O	Strong	Genetic Variation	[3]
Schizophrenia	DISSRV2N	moderate	Altered Expression	[4]
Obsolete severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency	DISS963W	Supportive	Autosomal recessive	[5]
Combined oxidative phosphorylation deficiency 19	DISHLDK4	Limited	Unknown	[5]
Crohn disease	DIS2C5Q8	Limited	Genetic Variation	[6]

4 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 LYR motif-containing protein 4 (LYRM4).	[7]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of LYR motif-containing protein 4 (LYRM4).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of LYR motif-containing protein 4 (LYRM4).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of LYR motif-containing protein 4 (LYRM4).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of LYR motif-containing protein 4 (LYRM4).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of LYR motif-containing protein 4 (LYRM4).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of LYR motif-containing protein 4 (LYRM4).	[10]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of LYR motif-containing protein 4 (LYRM4).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of LYR motif-containing protein 4 (LYRM4).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of LYR motif-containing protein 4 (LYRM4).	[15]

References

• [1] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [2] Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex and multiple mitochondrial chaperones.Hum Mol Genet. 2007 Apr 15;16(8):929-41. doi: 10.1093/hmg/ddm038. Epub 2007 Mar 1.
• [3] Investigation of Crohn's disease risk loci in ulcerative colitis further defines their molecular relationship.Gastroenterology. 2009 Feb;136(2):523-9.e3. doi: 10.1053/j.gastro.2008.10.032. Epub 2008 Oct 25.
• [4] 6p25 interstitial deletion in two dizygotic twins with gyral pattern anomaly and speech and language disorder.Eur J Paediatr Neurol. 2013 May;17(3):225-31. doi: 10.1016/j.ejpn.2012.09.008. Epub 2012 Oct 12.
• [5] Mutations in LYRM4, encoding iron-sulfur cluster biogenesis factor ISD11, cause deficiency of multiple respiratory chain complexes. Hum Mol Genet. 2013 Nov 15;22(22):4460-73. doi: 10.1093/hmg/ddt295. Epub 2013 Jun 28.
• [6] Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease.Nat Genet. 2008 Aug;40(8):955-62. doi: 10.1038/ng.175. Epub 2008 Jun 29.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.