Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY3BOF6)

• DOT Name: Zinc phosphodiesterase ELAC protein 2 (ELAC2)
• Synonyms: EC 3.1.26.11; ElaC homolog protein 2; Heredity prostate cancer protein 2; Ribonuclease Z 2; RNase Z 2; tRNA 3 endonuclease 2; tRNase Z 2
• Gene Name: ELAC2
• Related Disease:
  Mitochondrial complex I deficiency, nuclear type 1
  Mitochondrial disease
  Advanced cancer
  Benign prostatic hyperplasia
  Breast carcinoma
  Combined oxidative phosphorylation defect type 17
  Familial prostate carcinoma
  Hereditary chronic pancreatitis
  Intellectual disability
  Metastatic prostate carcinoma
  Mitochondrial complex I deficiency
  Non-small-cell lung cancer
  Pure red-cell aplasia
  Small-cell lung cancer
  Benign neoplasm
  Neoplasm
  Dilated cardiomyopathy
  Hypertrophic cardiomyopathy
  Lactic acidosis
  Prostate neoplasm
• UniProt ID: RNZ2_HUMAN
• EC Number: 3.1.26.11
• Pfam ID: PF12706 ; PF13691
• Sequence:
  MWALCSLLRSAAGRTMSQGRTISQAPARRERPRKDPLRHLRTREKRGPSGCSGGPNTVYL
  QVVAAGSRDSGAALYVFSEFNRYLFNCGEGVQRLMQEHKLKVARLDNIFLTRMHWSNVGG
  LSGMILTLKETGLPKCVLSGPPQLEKYLEAIKIFSGPLKGIELAVRPHSAPEYEDETMTV
  YQIPIHSEQRRGKHQPWQSPERPLSRLSPERSSDSESNENEPHLPHGVSQRRGVRDSSLV
  VAFICKLHLKRGNFLVLKAKEMGLPVGTAAIAPIIAAVKDGKSITHEGREILAEELCTPP
  DPGAAFVVVECPDESFIQPICENATFQRYQGKADAPVALVVHMAPASVLVDSRYQQWMER
  FGPDTQHLVLNENCASVHNLRSHKIQTQLNLIHPDIFPLLTSFRCKKEGPTLSVPMVQGE
  CLLKYQLRPRREWQRDAIITCNPEEFIVEALQLPNFQQSVQEYRRSAQDGPAPAEKRSQY
  PEIIFLGTGSAIPMKIRNVSATLVNISPDTSLLLDCGEGTFGQLCRHYGDQVDRVLGTLA
  AVFVSHLHADHHTGLPSILLQRERALASLGKPLHPLLVVAPNQLKAWLQQYHNQCQEVLH
  HISMIPAKCLQEGAEISSPAVERLISSLLRTCDLEEFQTCLVRHCKHAFGCALVHTSGWK
  VVYSGDTMPCEALVRMGKDATLLIHEATLEDGLEEEAVEKTHSTTSQAISVGMRMNAEFI
  MLNHFSQRYAKVPLFSPNFSEKVGVAFDHMKVCFGDFPTMPKLIPPLKALFAGDIEEMEE
  RREKRELRQVRAALLSRELAGGLEDGEPQQKRAHTEEPQAKKVRAQ
• Function: Zinc phosphodiesterase, which displays mitochondrial tRNA 3'-processing endonuclease activity. Involved in tRNA maturation, by removing a 3'-trailer from precursor tRNA. Associates with mitochondrial DNA complexes at the nucleoids to initiate RNA processing and ribosome assembly.
• Tissue Specificity: Widely expressed. Highly expressed in heart, placenta, liver, skeletal muscle, kidney, pancreas, testis and ovary. Weakly expressed in brain, lung, spleen, thymus, prostate, small intestine, colon and leukocytes.
• Reactome Pathway:
  tRNA processing in the mitochondrion (R-HSA-6785470)
  rRNA processing in the mitochondrion (R-HSA-8868766)
  tRNA-derived small RNA (tsRNA or tRNA-related fragment, tRF) biogenesis (R-HSA-9708296)
  tRNA processing in the nucleus (R-HSA-6784531)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial complex I deficiency, nuclear type 1	DISCPLX4	Definitive	Autosomal recessive	[1]
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Benign prostatic hyperplasia	DISI3CW2	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Combined oxidative phosphorylation defect type 17	DISAW6AL	Strong	Autosomal recessive	[5]
Familial prostate carcinoma	DISL9KNO	Strong	Biomarker	[6]
Hereditary chronic pancreatitis	DISF0J1Q	Strong	Biomarker	[7]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[8]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Genetic Variation	[9]
Mitochondrial complex I deficiency	DIS13M7V	Strong	Biomarker	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Pure red-cell aplasia	DIST91OT	Strong	Genetic Variation	[11]
Small-cell lung cancer	DISK3LZD	Strong	Biomarker	[10]
Benign neoplasm	DISDUXAD	moderate	Genetic Variation	[12]
Neoplasm	DISZKGEW	moderate	Altered Expression	[13]
Dilated cardiomyopathy	DISX608J	Disputed	Genetic Variation	[14]
Hypertrophic cardiomyopathy	DISQG2AI	Limited	Genetic Variation	[15]
Lactic acidosis	DISZI1ZK	Limited	Genetic Variation	[15]
Prostate neoplasm	DISHDKGQ	Limited	Genetic Variation	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Zinc phosphodiesterase ELAC protein 2 (ELAC2).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Zinc phosphodiesterase ELAC protein 2 (ELAC2).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Zinc phosphodiesterase ELAC protein 2 (ELAC2).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Zinc phosphodiesterase ELAC protein 2 (ELAC2).	[20]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Zinc phosphodiesterase ELAC protein 2 (ELAC2).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Zinc phosphodiesterase ELAC protein 2 (ELAC2).	[22]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Zinc phosphodiesterase ELAC protein 2 (ELAC2).	[24]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Zinc phosphodiesterase ELAC protein 2 (ELAC2).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Zinc phosphodiesterase ELAC protein 2 (ELAC2).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Zinc phosphodiesterase ELAC protein 2 (ELAC2).	[30]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Zinc phosphodiesterase ELAC protein 2 (ELAC2).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Zinc phosphodiesterase ELAC protein 2 (ELAC2).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Zinc phosphodiesterase ELAC protein 2 (ELAC2).	[27]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Zinc phosphodiesterase ELAC protein 2 (ELAC2).	[28]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Zinc phosphodiesterase ELAC protein 2 (ELAC2).	[29]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Zinc phosphodiesterase ELAC protein 2 (ELAC2).	[29]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Zinc phosphodiesterase ELAC protein 2 (ELAC2).	[26]

References

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• [2] 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.
• [3] Polymorphisms in the HPC/ELAC-2 and alpha 1-antitrypsin genes that correlate with human diseases in a North Indian population.Mol Biol Rep. 2011 Jun;38(5):3137-44. doi: 10.1007/s11033-010-9984-6. Epub 2010 Feb 2.
• [4] Implication of polycomb members Bmi-1, Mel-18, and Hpc-2 in the regulation of p16INK4a, p14ARF, h-TERT, and c-Myc expression in primary breast carcinomas.Clin Cancer Res. 2006 Dec 1;12(23):6929-36. doi: 10.1158/1078-0432.CCR-06-0788.
• [5] HIV-positive women: reasons they are tested for HIV and their clinical characteristics on entry into the health care system. J Gen Intern Med. 1991 Jul-Aug;6(4):286-9. doi: 10.1007/BF02597422.
• [6] Germline genetic profiling in prostate cancer: latest developments and potential clinical applications.Future Sci OA. 2015 Dec 18;2(1):FSO87. doi: 10.4155/fso.15.87. eCollection 2016 Mar.
• [7] HPC2/ELAC2 gene variants associated with incident prostate cancer.J Hum Genet. 2003;48(12):634-638. doi: 10.1007/s10038-003-0091-6. Epub 2003 Nov 19.
• [8] A homozygous splicing mutation in ELAC2 suggests phenotypic variability including intellectual disability with minimal cardiac involvement.Orphanet J Rare Dis. 2016 Oct 21;11(1):139. doi: 10.1186/s13023-016-0526-8.
• [9] Association of hereditary prostate cancer gene polymorphic variants with sporadic aggressive prostate carcinoma.Prostate. 2006 Jan 1;66(1):49-56. doi: 10.1002/pros.20320.
• [10] Lung Cancer-Targeting Peptides with Multi-subtype Indication for Combinational Drug Delivery and Molecular Imaging.Theranostics. 2017 Apr 10;7(6):1612-1632. doi: 10.7150/thno.17573. eCollection 2017.
• [11] ELAC2/HPC2 involvement in hereditary and sporadic prostate cancer.Cancer Res. 2001 Aug 15;61(16):6038-41.
• [12] Associations of polymorphisms in HPC2/ELAC2 and SRD5A2 genes with benign prostate hyperplasia in Turkish men.Asian Pac J Cancer Prev. 2011;12(3):731-3.
• [13] Nuclear ELAC2 overexpression is associated with increased hazard for relapse after radical prostatectomy.Oncotarget. 2019 Aug 13;10(48):4973-4986. doi: 10.18632/oncotarget.27132. eCollection 2019 Aug 13.
• [14] Concerted regulation of mitochondrial and nuclear non-coding RNAs by a dual-targeted RNase Z.EMBO Rep. 2018 Oct;19(10):e46198. doi: 10.15252/embr.201846198. Epub 2018 Aug 20.
• [15] Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3'-end processing.Hum Mutat. 2019 Oct;40(10):1731-1748. doi: 10.1002/humu.23777. Epub 2019 Jun 18.
• [16] Sequence variants of elaC homolog 2 (Escherichia coli) (ELAC2) gene and susceptibility to prostate cancer in the Health Professionals Follow-Up Study.Carcinogenesis. 2008 May;29(5):999-1004. doi: 10.1093/carcin/bgn081. Epub 2008 Mar 28.
• [17] 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.
• [18] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [19] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] Bisphenol-A and estradiol exert novel gene regulation in human MCF-7 derived breast cancer cells. Mol Cell Endocrinol. 2004 Jun 30;221(1-2):47-55. doi: 10.1016/j.mce.2004.04.010.
• [22] 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.
• [23] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [24] 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.
• [25] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [26] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [27] 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.
• [28] 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.
• [29] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [30] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [31] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.