Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPYQX3K)

• DOT Name: Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP)
• Synonyms: ASF/SF2-associated protein p32; Glycoprotein gC1qBP; C1qBP; Hyaluronan-binding protein 1; Mitochondrial matrix protein p32; gC1q-R protein; p33; SF2AP32
• Gene Name: C1QBP
• Related Disease:
  Mitochondrial disease
  Combined oxidative phosphorylation deficiency 33
• UniProt ID: C1QBP_HUMAN
• PDB ID: 1P32; 3RPX; 6SZW; 7TE3
• Pfam ID: PF02330
• Sequence:
  MLPLLRCVPRVLGSSVAGLRAAAPASPFRQLLQPAPRLCTRPFGLLSVRAGSERRPGLLR
  PRGPCACGCGCGSLHTDGDKAFVDFLSDEIKEERKIQKHKTLPKMSGGWELELNGTEAKL
  VRKVAGEKITVTFNINNSIPPTFDGEEEPSQGQKVEEQEPELTSTPNFVVEVIKNDDGKK
  ALVLDCHYPEDEVGQEDEAESDIFSIREVSFQSTGESEWKDTNYTLNTDSLDWALYDHLM
  DFLADRGVDNTFADELVELSTALEHQEYITFLEDLKSFVKSQ
• Function: Is believed to be a multifunctional and multicompartmental protein involved in inflammation and infection processes, ribosome biogenesis, protein synthesis in mitochondria, regulation of apoptosis, transcriptional regulation and pre-mRNA splicing. At the cell surface is thought to act as an endothelial receptor for plasma proteins of the complement and kallikrein-kinin cascades. Putative receptor for C1q; specifically binds to the globular 'heads' of C1q thus inhibiting C1; may perform the receptor function through a complex with C1qR/CD93. In complex with cytokeratin-1/KRT1 is a high affinity receptor for kininogen-1/HMWK. Can also bind other plasma proteins, such as coagulation factor XII leading to its autoactivation. May function to bind initially fluid kininogen-1 to the cell membrane. The secreted form may enhance both extrinsic and intrinsic coagulation pathways. It is postulated that the cell surface form requires docking with transmembrane proteins for downstream signaling which might be specific for a cell-type or response. By acting as C1q receptor is involved in chemotaxis of immature dendritic cells and neutrophils and is proposed to signal through CD209/DC-SIGN on immature dendritic cells, through integrin alpha-4/beta-1 during trophoblast invasion of the decidua, and through integrin beta-1 during endothelial cell adhesion and spreading. Signaling involved in inhibition of innate immune response is implicating the PI3K-AKT/PKB pathway. Required for protein synthesis in mitochondria. In mitochondrial translation may be involved in formation of functional 55S mitoribosomes; the function seems to involve its RNA-binding activity. May be involved in the nucleolar ribosome maturation process; the function may involve the exchange of FBL for RRP1 in the association with pre-ribosome particles. Involved in regulation of RNA splicing by inhibiting the RNA-binding capacity of SRSF1 and its phosphorylation. Is required for the nuclear translocation of splicing factor U2AF1L4. Involved in regulation of CDKN2A- and HRK-mediated apoptosis. Stabilizes mitochondrial CDKN2A isoform smARF. May be involved in regulation of FOXC1 transcriptional activity and NFY/CCAAT-binding factor complex-mediated transcription. May play a role in antibacterial defense as it can bind to cell surface hyaluronan and inhibit Streptococcus pneumoniae hyaluronate lyase. May be involved in modulation of the immune response; ligation by HCV core protein is resulting in suppression of interleukin-12 production in monocyte-derived dendritic cells. Involved in regulation of antiviral response by inhibiting RIGI- and IFIH1-mediated signaling pathways probably involving its association with MAVS after viral infection; (Microbial infection) Involved in HIV-1 replication, presumably by contributing to splicing of viral RNA; (Microbial infection) In infection processes acts as an attachment site for microbial proteins, including Listeria monocytogenes internalin B (InlB) and Staphylococcus aureus protein A; (Microbial infection) Involved in replication of Rubella virus.
• Tissue Specificity: Expressed on cell surface of peripheral blood cells (at protein level); Surface expression is reported for macrophages and monocyte-derived dendritic cells.
• Reactome Pathway:
  Intrinsic Pathway of Fibrin Clot Formation (R-HSA-140837)
  RHOA GTPase cycle (R-HSA-8980692)
  RHOC GTPase cycle (R-HSA-9013106)
  Defective Intrinsic Pathway for Apoptosis Due to p14ARF Loss of Function (R-HSA-9645722)
  Apoptotic factor-mediated response (R-HSA-111471)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[1]
Combined oxidative phosphorylation deficiency 33	DIS2J5JN	Strong	Autosomal recessive	[2]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP) decreases the response to substance of Methotrexate.	[21]
Etoposide	DMNH3PG	Approved	Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP) decreases the response to substance of Etoposide.	[21]
Dactinomycin	DM2YGNW	Approved	Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP) decreases the response to substance of Dactinomycin.	[21]
Floxuridine	DM04LR2	Approved	Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP) decreases the response to substance of Floxuridine.	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP).	[9]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP).	[10]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP).	[9]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP).	[11]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP).	[12]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline decreases the expression of Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP).	[13]
Dopamine	DMPGUCF	Approved	Dopamine increases the expression of Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP).	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP).	[19]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP).	[17]

References

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• [10] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [11] Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis. J Cell Biochem. 2017 Apr;118(4):819-828. doi: 10.1002/jcb.25757. Epub 2016 Nov 28.
• [12] Effects of acute ethanol treatment on NCCIT cells and NCCIT cell-derived embryoid bodies (EBs). Toxicol In Vitro. 2010 Sep;24(6):1696-704. doi: 10.1016/j.tiv.2010.05.017. Epub 2010 May 26.
• [13] Controlled diesel exhaust and allergen coexposure modulates microRNA and gene expression in humans: Effects on inflammatory lung markers. J Allergy Clin Immunol. 2016 Dec;138(6):1690-1700. doi: 10.1016/j.jaci.2016.02.038. Epub 2016 Apr 24.
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• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] 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.
• [18] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [19] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [20] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [21] [Expression of C1QBP gene and its correlation with drug resistance in human resistance choriocarcinoma cell line]. Zhonghua Fu Chan Ke Za Zhi. 2014 Aug;49(8):616-20.