Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGZ51QF)

• DOT Name: Reticulon-3 (RTN3)
• Synonyms: Homolog of ASY protein; HAP; Neuroendocrine-specific protein-like 2; NSP-like protein 2; Neuroendocrine-specific protein-like II; NSP-like protein II; NSPLII
• Gene Name: RTN3
• Related Disease:
  Cognitive impairment
  Melanoma
  Pneumonia
  Skin cancer
  Alzheimer disease
  Amyloidosis
  Anemia
  Autism spectrum disorder
  Carcinoma of liver and intrahepatic biliary tract
  Hepatitis C virus infection
  Influenza
  Liver cancer
  Obesity
  Schizoaffective disorder
  Graft-versus-host disease
  Hepatocellular carcinoma
  Lupus nephritis
  Methicillin-resistant staphylococci infection
  Pancreatic cancer
  Bipolar I disorder
  Neoplasm
  Psychotic disorder
• UniProt ID: RTN3_HUMAN
• PDB ID: 7BRU
• Pfam ID: PF02453
• Sequence:
  MAEPSAATQSHSISSSSFGAEPSAPGGGGSPGACPALGTKSCSSSCADSFVSSSSSQPVS
  LFSTSQEGLSSLCSDEPSSEIMTSSFLSSSEIHNTGLTILHGEKSHVLGSQPILAKEGKD
  HLDLLDMKKMEKPQGTSNNVSDSSVSLAAGVHCDRPSIPASFPEHPAFLSKKIGQVEEQI
  DKETKNPNGVSSREAKTALDADDRFTLLTAQKPPTEYSKVEGIYTYSLSPSKVSGDDVIE
  KDSPESPFEVIIDKAAFDKEFKDSYKESTDDFGSWSVHTDKESSEDISETNDKLFPLRNK
  EAGRYPMSALLSRQFSHTNAALEEVSRCVNDMHNFTNEILTWDLVPQVKQQTDKSSDCIT
  KTTGLDMSEYNSEIPVVNLKTSTHQKTPVCSIDGSTPITKSTGDWAEASLQQENAITGKP
  VPDSLNSTKEFSIKGVQGNMQKQDDTLAELPGSPPEKCDSLGSGVATVKVVLPDDHLKDE
  MDWQSSALGEITEADSSGESDDTVIEDITADTSFENNKIQAEKPVSIPSAVVKTGEREIK
  EIPSCEREEKTSKNFEELVSDSELHQDQPDILGRSPASEAACSKVPDTNVSLEDVSEVAP
  EKPITTENPKLPSTVSPNVFNETEFSLNVTTSAYLESLHGKNVKHIDDSSPEDLIAAFTE
  TRDKGIVDSERNAFKAISEKMTDFKTTPPVEVLHENESGGSEIKDIGSKYSEQSKETNGS
  EPLGVFPTQGTPVASLDLEQEQLTIKALKELGERQVEKSTSAQRDAELPSEEVLKQTFTF
  APESWPQRSYDILERNVKNGSDLGISQKPITIRETTRVDAVSSLSKTELVKKHVLARLLT
  DFSVHDLIFWRDVKKTGFVFGTTLIMLLSLAAFSVISVVSYLILALLSVTISFRIYKSVI
  QAVQKSEEGHPFKAYLDVDITLSSEAFHNYMNAAMVHINRALKLIIRLFLVEDLVDSLKL
  AVFMWLMTYVGAVFNGITLLILAELLIFSVPIVYEKYKTQIDHYVGIARDQTKSIVEKIQ
  AKLPGIAKKKAE
• Function: May be involved in membrane trafficking in the early secretory pathway. Inhibits BACE1 activity and amyloid precursor protein processing. May induce caspase-8 cascade and apoptosis. May favor BCL2 translocation to the mitochondria upon endoplasmic reticulum stress. Induces the formation of endoplasmic reticulum tubules. Also acts as an inflammation-resolving regulator by interacting with both TRIM25 and RIGI, subsequently impairing RIGI 'Lys-63'-linked polyubiquitination leading to IRF3 and NF-kappa-B inhibition; (Microbial infection) Plays a positive role in viral replication and pathogenesis of enteroviruses.
• Tissue Specificity: Isoform 3 is widely expressed, with highest levels in brain, where it is enriched in neuronal cell bodies from gray matter (at protein level). Three times more abundant in macula than in peripheral retina. Isoform 1 is expressed at high levels in brain and at low levels in skeletal muscle. Isoform 2 is only found in melanoma.
• KEGG Pathway: Alzheimer disease (hsa05010)
• Reactome Pathway: Synaptic adhesion-like molecules (R-HSA-8849932)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cognitive impairment	DISH2ERD	Definitive	Altered Expression	[1]
Melanoma	DIS1RRCY	Definitive	Biomarker	[2]
Pneumonia	DIS8EF3M	Definitive	Biomarker	[3]
Skin cancer	DISTM18U	Definitive	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Amyloidosis	DISHTAI2	Strong	Biomarker	[5]
Anemia	DISTVL0C	Strong	Genetic Variation	[6]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[7]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[8]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[9]
Influenza	DIS3PNU3	Strong	Genetic Variation	[10]
Liver cancer	DISDE4BI	Strong	Biomarker	[8]
Obesity	DIS47Y1K	Strong	Biomarker	[11]
Schizoaffective disorder	DISLBW6B	Strong	Genetic Variation	[12]
Graft-versus-host disease	DIS0QADF	moderate	Biomarker	[13]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[8]
Lupus nephritis	DISCVGPZ	moderate	Biomarker	[14]
Methicillin-resistant staphylococci infection	DIS6DRDZ	moderate	Biomarker	[15]
Pancreatic cancer	DISJC981	moderate	Biomarker	[16]
Bipolar I disorder	DISD09EH	Limited	Genetic Variation	[17]
Neoplasm	DISZKGEW	Limited	Biomarker	[2]
Psychotic disorder	DIS4UQOT	Limited	Genetic Variation	[17]

14 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 Reticulon-3 (RTN3).	[18]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Reticulon-3 (RTN3).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Reticulon-3 (RTN3).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Reticulon-3 (RTN3).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Reticulon-3 (RTN3).	[22]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Reticulon-3 (RTN3).	[23]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Reticulon-3 (RTN3).	[24]
Marinol	DM70IK5	Approved	Marinol increases the expression of Reticulon-3 (RTN3).	[25]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Reticulon-3 (RTN3).	[26]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Reticulon-3 (RTN3).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Reticulon-3 (RTN3).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Reticulon-3 (RTN3).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Reticulon-3 (RTN3).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Reticulon-3 (RTN3).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Reticulon-3 (RTN3).	[30]

References

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• [21] 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.
• [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] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
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