Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRGSR6B)

• DOT Name: Ketimine reductase mu-crystallin (CRYM)
• Synonyms: EC 1.5.1.25; NADP-regulated thyroid-hormone-binding protein
• Gene Name: CRYM
• Related Disease:
  Advanced cancer
  Cataract
  Hypogonadism
  Schizophrenia
  Autosomal dominant nonsyndromic hearing loss 40
  Autosomal dominant nonsyndromic hearing loss
  Amyotrophic lateral sclerosis
  Deafness
  facioscapulohumeral muscular dystrophy
  Neoplasm
  Nonsyndromic genetic hearing loss
• UniProt ID: CRYM_HUMAN
• PDB ID: 2I99
• EC Number: 1.5.1.25
• Pfam ID: PF02423
• Sequence:
  MSRVPAFLSAAEVEEHLRSSSLLIPPLETALANFSSGPEGGVMQPVRTVVPVTKHRGYLG
  VMPAYSAAEDALTTKLVTFYEDRGITSVVPSHQATVLLFEPSNGTLLAVMDGNVITAKRT
  AAVSAIATKFLKPPSSEVLCILGAGVQAYSHYEIFTEQFSFKEVRIWNRTKENAEKFADT
  VQGEVRVCSSVQEAVAGADVIITVTLATEPILFGEWVKPGAHINAVGASRPDWRELDDEL
  MKEAVLYVDSQEAALKESGDVLLSGAEIFAELGEVIKGVKPAHCEKTTVFKSLGMAVEDT
  VAAKLIYDSWSSGK
• Function: Specifically catalyzes the reduction of imine bonds in brain substrates that may include cystathionine ketimine (CysK) and lanthionine ketimine (LK). Binds thyroid hormone which is a strong reversible inhibitor. Presumably involved in the regulation of the free intracellular concentration of triiodothyronine and access to its nuclear receptors.
• Tissue Specificity: Expressed in neural tissue, muscle and kidney.
• Reactome Pathway: Lysine catabolism (R-HSA-71064)
• BioCyc Pathway: MetaCyc:ENSG00000103316-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Cataract	DISUD7SL	Strong	Genetic Variation	[2]
Hypogonadism	DISICMNI	Strong	Biomarker	[3]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[4]
Autosomal dominant nonsyndromic hearing loss 40	DISWH1QV	Moderate	Autosomal dominant	[5]
Autosomal dominant nonsyndromic hearing loss	DISYC1G0	Supportive	Autosomal dominant	[6]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[7]
Deafness	DISKCLH4	Limited	Altered Expression	[5]
facioscapulohumeral muscular dystrophy	DISSE0H0	Limited	Altered Expression	[8]
Neoplasm	DISZKGEW	Limited	Altered Expression	[9]
Nonsyndromic genetic hearing loss	DISZX61P	Limited	Autosomal dominant	[10]

16 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 Ketimine reductase mu-crystallin (CRYM).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ketimine reductase mu-crystallin (CRYM).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ketimine reductase mu-crystallin (CRYM).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ketimine reductase mu-crystallin (CRYM).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ketimine reductase mu-crystallin (CRYM).	[15]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Ketimine reductase mu-crystallin (CRYM).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ketimine reductase mu-crystallin (CRYM).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ketimine reductase mu-crystallin (CRYM).	[18]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Ketimine reductase mu-crystallin (CRYM).	[19]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ketimine reductase mu-crystallin (CRYM).	[20]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of Ketimine reductase mu-crystallin (CRYM).	[21]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Ketimine reductase mu-crystallin (CRYM).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Ketimine reductase mu-crystallin (CRYM).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ketimine reductase mu-crystallin (CRYM).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ketimine reductase mu-crystallin (CRYM).	[24]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Ketimine reductase mu-crystallin (CRYM).	[25]

References

• [1] Identification of mu-crystallin as an androgen-regulated gene in human prostate cancer.Prostate. 2009 Jul 1;69(10):1109-18. doi: 10.1002/pros.20956.
• [2] Genetics of crystallins: cataract and beyond.Exp Eye Res. 2009 Feb;88(2):173-89. doi: 10.1016/j.exer.2008.10.011. Epub 2008 Nov 1.
• [3] Gene screening facilitates diagnosis of complicated symptoms: A case report.Mol Med Rep. 2017 Dec;16(6):7915-7922. doi: 10.3892/mmr.2017.7590. Epub 2017 Sep 22.
• [4] Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):151-63. doi: 10.1007/s00406-008-0847-2. Epub 2009 Jan 22.
• [5] Identification of CRYM as a candidate responsible for nonsyndromic deafness, through cDNA microarray analysis of human cochlear and vestibular tissues. Am J Hum Genet. 2003 Jan;72(1):73-82. doi: 10.1086/345398. Epub 2002 Dec 6.
• [6] [Gene therapy for human hearing loss: challenges and promises]. Med Sci (Paris). 2013 Oct;29(10):883-9. doi: 10.1051/medsci/20132910016. Epub 2013 Oct 18.
• [7] Resequencing of 29 candidate genes in patients with familial and sporadic amyotrophic lateral sclerosis.Arch Neurol. 2011 May;68(5):587-93. doi: 10.1001/archneurol.2010.351. Epub 2011 Jan 10.
• [8] Abnormal expression of mu-crystallin in facioscapulohumeral muscular dystrophy.Exp Neurol. 2007 Jun;205(2):583-6. doi: 10.1016/j.expneurol.2007.03.009. Epub 2007 Mar 21.
• [9] Clinical validation of candidate genes associated with prostate cancer progression in the CWR22 model system using tissue microarrays.Cancer Res. 2002 Mar 1;62(5):1256-60.
• [10] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [11] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [12] 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.
• [13] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [14] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [15] 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.
• [16] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [17] 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.
• [18] 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.
• [19] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [20] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [21] 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.
• [22] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [23] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [24] 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.
• [25] 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.