Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4JY32Q)

• DOT Name: Protein argonaute-2 (AGO2)
• Synonyms: Argonaute2; hAgo2; EC 3.1.26.n2; Argonaute RISC catalytic component 2; Eukaryotic translation initiation factor 2C 2; eIF-2C 2; eIF2C 2; PAZ Piwi domain protein; PPD; Protein slicer
• Gene Name: AGO2
• Related Disease:
  Lessel-Kreienkamp syndrome
  Advanced cancer
  Alcohol dependence
  Bladder cancer
  Breast neoplasm
  Carcinoma
  Classic Hodgkin lymphoma
  Colon cancer
  Colon carcinoma
  Cytomegalovirus infection
  Epithelial ovarian cancer
  Familial hypercholesterolemia
  Gastric cancer
  Glioblastoma multiforme
  Glioma
  Hepatitis B virus infection
  Hepatitis C virus infection
  Huntington disease
  Hypercholesterolemia, familial, 1
  Hypothyroidism
  Latent tuberculosis infection
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Malignant mesothelioma
  Neoplasm
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic cancer
  Plasma cell myeloma
  Progressive pseudorheumatoid arthropathy of childhood
  Prostate cancer
  Prostate carcinoma
  Schizophrenia
  Urinary bladder cancer
  Urinary bladder neoplasm
  Clear cell renal carcinoma
  Melanoma
  Myeloid leukaemia
  Neuroblastoma
  Asthma
  Cocaine addiction
  Colorectal carcinoma
  Pallister-Hall syndrome
  Parkinson disease
  Renal cell carcinoma
  Stomach cancer
• UniProt ID: AGO2_HUMAN
• PDB ID: 3LUC ; 3LUD ; 3LUG ; 3LUH ; 3LUJ ; 3LUK ; 3QX8 ; 3QX9 ; 4F3T ; 4OLA ; 4OLB ; 4W5N ; 4W5O ; 4W5Q ; 4W5R ; 4W5T ; 4Z4C ; 4Z4D ; 4Z4E ; 4Z4F ; 4Z4G ; 4Z4H ; 4Z4I ; 5JS1 ; 5JS2 ; 5KI6 ; 5T7B ; 5WEA ; 6CBD ; 6MDZ ; 6MFN ; 6MFR ; 6N4O ; 6NIT ; 6RA4 ; 7C6B ; 7D7U ; 7KI3 ; 8D6J ; 8D71
• EC Number: 3.1.26.n2
• Pfam ID: PF08699 ; PF16488 ; PF16487 ; PF16486 ; PF02170 ; PF02171
• Sequence:
  MYSGAGPALAPPAPPPPIQGYAFKPPPRPDFGTSGRTIKLQANFFEMDIPKIDIYHYELD
  IKPEKCPRRVNREIVEHMVQHFKTQIFGDRKPVFDGRKNLYTAMPLPIGRDKVELEVTLP
  GEGKDRIFKVSIKWVSCVSLQALHDALSGRLPSVPFETIQALDVVMRHLPSMRYTPVGRS
  FFTASEGCSNPLGGGREVWFGFHQSVRPSLWKMMLNIDVSATAFYKAQPVIEFVCEVLDF
  KSIEEQQKPLTDSQRVKFTKEIKGLKVEITHCGQMKRKYRVCNVTRRPASHQTFPLQQES
  GQTVECTVAQYFKDRHKLVLRYPHLPCLQVGQEQKHTYLPLEVCNIVAGQRCIKKLTDNQ
  TSTMIRATARSAPDRQEEISKLMRSASFNTDPYVREFGIMVKDEMTDVTGRVLQPPSILY
  GGRNKAIATPVQGVWDMRNKQFHTGIEIKVWAIACFAPQRQCTEVHLKSFTEQLRKISRD
  AGMPIQGQPCFCKYAQGADSVEPMFRHLKNTYAGLQLVVVILPGKTPVYAEVKRVGDTVL
  GMATQCVQMKNVQRTTPQTLSNLCLKINVKLGGVNNILLPQGRPPVFQQPVIFLGADVTH
  PPAGDGKKPSIAAVVGSMDAHPNRYCATVRVQQHRQEIIQDLAAMVRELLIQFYKSTRFK
  PTRIIFYRDGVSEGQFQQVLHHELLAIREACIKLEKDYQPGITFIVVQKRHHTRLFCTDK
  NERVGKSGNIPAGTTVDTKITHPTEFDFYLCSHAGIQGTSRPSHYHVLWDDNRFSSDELQ
  ILTYQLCHTYVRCTRSVSIPAPAYYAHLVAFRARYHLVDKEHDSAEGSHTSGQSNGRDHQ
  ALAKAVQVHQDTLRTMYFA
• Function: Required for RNA-mediated gene silencing (RNAi) by the RNA-induced silencing complex (RISC). The 'minimal RISC' appears to include AGO2 bound to a short guide RNA such as a microRNA (miRNA) or short interfering RNA (siRNA). These guide RNAs direct RISC to complementary mRNAs that are targets for RISC-mediated gene silencing. The precise mechanism of gene silencing depends on the degree of complementarity between the miRNA or siRNA and its target. Binding of RISC to a perfectly complementary mRNA generally results in silencing due to endonucleolytic cleavage of the mRNA specifically by AGO2. Binding of RISC to a partially complementary mRNA results in silencing through inhibition of translation, and this is independent of endonuclease activity. May inhibit translation initiation by binding to the 7-methylguanosine cap, thereby preventing the recruitment of the translation initiation factor eIF4-E. May also inhibit translation initiation via interaction with EIF6, which itself binds to the 60S ribosomal subunit and prevents its association with the 40S ribosomal subunit. The inhibition of translational initiation leads to the accumulation of the affected mRNA in cytoplasmic processing bodies (P-bodies), where mRNA degradation may subsequently occur. In some cases RISC-mediated translational repression is also observed for miRNAs that perfectly match the 3' untranslated region (3'-UTR). Can also up-regulate the translation of specific mRNAs under certain growth conditions. Binds to the AU element of the 3'-UTR of the TNF (TNF-alpha) mRNA and up-regulates translation under conditions of serum starvation. Also required for transcriptional gene silencing (TGS), in which short RNAs known as antigene RNAs or agRNAs direct the transcriptional repression of complementary promoter regions; (Microbial infection) Upon Sars-CoV-2 infection, associates with viral miRNA-like small RNA, CoV2-miR-O7a, and may repress mRNAs, such as BATF2, to evade the IFN response.
• Reactome Pathway:
  MicroRNA (miRNA) biogenesis (R-HSA-203927)
  Ca2+ pathway (R-HSA-4086398)
  Small interfering RNA (siRNA) biogenesis (R-HSA-426486)
  Post-transcriptional silencing by small RNAs (R-HSA-426496)
  Transcriptional regulation by small RNAs (R-HSA-5578749)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)
  MAPK6/MAPK4 signaling (R-HSA-5687128)
  Regulation of RUNX1 Expression and Activity (R-HSA-8934593)
  Regulation of PTEN mRNA translation (R-HSA-8943723)
  Competing endogenous RNAs (ceRNAs) regulate PTEN translation (R-HSA-8948700)
  Transcriptional Regulation by MECP2 (R-HSA-8986944)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Regulation of MECP2 expression and activity (R-HSA-9022692)
  NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux (R-HSA-9029569)
  Regulation of CDH11 mRNA translation by microRNAs (R-HSA-9759811)
  Regulation of NPAS4 mRNA translation (R-HSA-9768778)
  M-decay (R-HSA-9820841)
  Pre-NOTCH Transcription and Translation (R-HSA-1912408)

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lessel-Kreienkamp syndrome	DIS1IFVA	Definitive	Autosomal dominant	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alcohol dependence	DIS4ZSCO	Strong	Genetic Variation	[3]
Bladder cancer	DISUHNM0	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[5]
Carcinoma	DISH9F1N	Strong	Altered Expression	[4]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Genetic Variation	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[7]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[8]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[9]
Familial hypercholesterolemia	DISC06IX	Strong	Biomarker	[10]
Gastric cancer	DISXGOUK	Strong	Biomarker	[11]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[12]
Glioma	DIS5RPEH	Strong	Altered Expression	[13]
Hepatitis B virus infection	DISLQ2XY	Strong	Posttranslational Modification	[14]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[15]
Huntington disease	DISQPLA4	Strong	Genetic Variation	[6]
Hypercholesterolemia, familial, 1	DISU411W	Strong	Biomarker	[10]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[16]
Latent tuberculosis infection	DIS6R1EH	Strong	Biomarker	[17]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[18]
Lung cancer	DISCM4YA	Strong	Biomarker	[19]
Lung carcinoma	DISTR26C	Strong	Biomarker	[19]
Malignant mesothelioma	DISTHJGH	Strong	Biomarker	[20]
Neoplasm	DISZKGEW	Strong	Biomarker	[21]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[22]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[9]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[9]
Pancreatic cancer	DISJC981	Strong	Biomarker	[23]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[24]
Progressive pseudorheumatoid arthropathy of childhood	DISBMRIW	Strong	Altered Expression	[25]
Prostate cancer	DISF190Y	Strong	Biomarker	[26]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[26]
Schizophrenia	DISSRV2N	Strong	Biomarker	[27]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[28]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[28]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[29]
Melanoma	DIS1RRCY	moderate	Altered Expression	[30]
Myeloid leukaemia	DISMN944	moderate	Altered Expression	[31]
Neuroblastoma	DISVZBI4	Disputed	Altered Expression	[32]
Asthma	DISW9QNS	Limited	Biomarker	[33]
Cocaine addiction	DISHTRXG	Limited	Biomarker	[34]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[21]
Pallister-Hall syndrome	DISTYTPU	Limited	Biomarker	[35]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[36]
Renal cell carcinoma	DISQZ2X8	Limited	Biomarker	[29]
Stomach cancer	DISKIJSX	Limited	Biomarker	[11]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorothiazide	DMLHESP	Approved	Protein argonaute-2 (AGO2) increases the Metabolic disorder ADR of Chlorothiazide.	[62]

23 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 Protein argonaute-2 (AGO2).	[37]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein argonaute-2 (AGO2).	[38]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein argonaute-2 (AGO2).	[39]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein argonaute-2 (AGO2).	[40]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein argonaute-2 (AGO2).	[41]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein argonaute-2 (AGO2).	[42]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein argonaute-2 (AGO2).	[43]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein argonaute-2 (AGO2).	[44]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein argonaute-2 (AGO2).	[45]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Protein argonaute-2 (AGO2).	[47]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Protein argonaute-2 (AGO2).	[48]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Protein argonaute-2 (AGO2).	[49]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Protein argonaute-2 (AGO2).	[50]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein argonaute-2 (AGO2).	[51]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein argonaute-2 (AGO2).	[52]
Marinol	DM70IK5	Approved	Marinol increases the expression of Protein argonaute-2 (AGO2).	[53]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Protein argonaute-2 (AGO2).	[54]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Protein argonaute-2 (AGO2).	[56]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Protein argonaute-2 (AGO2).	[57]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Protein argonaute-2 (AGO2).	[52]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein argonaute-2 (AGO2).	[59]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Protein argonaute-2 (AGO2).	[60]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Protein argonaute-2 (AGO2).	[61]

4 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 Protein argonaute-2 (AGO2).	[46]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Protein argonaute-2 (AGO2).	[55]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Protein argonaute-2 (AGO2).	[58]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Protein argonaute-2 (AGO2).	[55]

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