Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHWE0NF)

• DOT Name: Reticulocalbin-3 (RCN3)
• Synonyms: EF-hand calcium-binding protein RLP49
• Gene Name: RCN3
• Related Disease:
  Pulmonary fibrosis
  Osteoarthritis
• UniProt ID: RCN3_HUMAN
• Pfam ID: PF13202 ; PF13499
• Sequence:
  MMWRPSVLLLLLLLRHGAQGKPSPDAGPHGQGRVHQAAPLSDAPHDDAHGNFQYDHEAFL
  GREVAKEFDQLTPEESQARLGRIVDRMDRAGDGDGWVSLAELRAWIAHTQQRHIRDSVSA
  AWDTYDTDRDGRVGWEELRNATYGHYAPGEEFHDVEDAETYKKMLARDERRFRVADQDGD
  SMATREELTAFLHPEEFPHMRDIVIAETLEDLDRNKDGYVQVEEYIADLYSAEPGEEEPA
  WVQTERQQFRDFRDLNKDGHLDGSEVGHWVLPPAQDQPLVEANHLLHESDTDKDGRLSKA
  EILGNWNMFVGSQATNYGEDLTRHHDEL
• Function: Probable molecular chaperone assisting protein biosynthesis and transport in the endoplasmic reticulum. Required for the proper biosynthesis and transport of pulmonary surfactant-associated protein A/SP-A, pulmonary surfactant-associated protein D/SP-D and the lipid transporter ABCA3. By regulating both the proper expression and the degradation through the endoplasmic reticulum-associated protein degradation pathway of these proteins plays a crucial role in pulmonary surfactant homeostasis. Has an anti-fibrotic activity by negatively regulating the secretion of type I and type III collagens. This calcium-binding protein also transiently associates with immature PCSK6 and regulates its secretion.
• Tissue Specificity: Widely expressed.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[1]
Osteoarthritis	DIS05URM	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Reticulocalbin-3 (RCN3).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Reticulocalbin-3 (RCN3).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Reticulocalbin-3 (RCN3).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Reticulocalbin-3 (RCN3).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Reticulocalbin-3 (RCN3).	[6]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Reticulocalbin-3 (RCN3).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Reticulocalbin-3 (RCN3).	[8]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Reticulocalbin-3 (RCN3).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Reticulocalbin-3 (RCN3).	[11]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Reticulocalbin-3 (RCN3).	[12]

References

• [1] Reticulocalbin 3 Deficiency in Alveolar Epithelium Exacerbated Bleomycin-induced Pulmonary Fibrosis.Am J Respir Cell Mol Biol. 2018 Sep;59(3):320-333. doi: 10.1165/rcmb.2017-0347OC.
• [2] Mitochondrial dysregulation of osteoarthritic human articular chondrocytes analyzed by proteomics: a decrease in mitochondrial superoxide dismutase points to a redox imbalance.Mol Cell Proteomics. 2009 Jan;8(1):172-89. doi: 10.1074/mcp.M800292-MCP200. Epub 2008 Sep 9.
• [3] 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.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] 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.
• [6] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [7] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [10] 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.
• [11] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [12] 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.