Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ70B0K)

• DOT Name: C4b-binding protein beta chain (C4BPB)
• Gene Name: C4BPB
• Related Disease:
  Familial hypercholesterolemia
  Hypercholesterolemia, familial, 1
  Non-small-cell lung cancer
  Advanced cancer
  Amyloidosis
  Autoimmune disease
  Behcet disease
  Complement component 4a deficiency
  Complement component 4b deficiency
  Epithelial ovarian cancer
  IgA nephropathy
  Protein S deficiency
  Ulcerative colitis
  Chronic obstructive pulmonary disease
  Pneumonia
  Pulmonary tuberculosis
  Gonorrhea
  Neoplasm
• UniProt ID: C4BPB_HUMAN
• Pfam ID: PF00084
• Sequence:
  MFFWCACCLMVAWRVSASDAEHCPELPPVDNSIFVAKEVEGQILGTYVCIKGYHLVGKKT
  LFCNASKEWDNTTTECRLGHCPDPVLVNGEFSSSGPVNVSDKITFMCNDHYILKGSNRSQ
  CLEDHTWAPPFPICKSRDCDPPGNPVHGYFEGNNFTLGSTISYYCEDRYYLVGVQEQQCV
  DGEWSSALPVCKLIQEAPKPECEKALLAFQESKNLCEAMENFMQQLKESGMTMEELKYSL
  ELKKAELKAKLL
• Function: Controls the classical pathway of complement activation. It binds as a cofactor to C3b/C4b inactivator (C3bINA), which then hydrolyzes the complement fragment C4b. It also accelerates the degradation of the C4bC2a complex (C3 convertase) by dissociating the complement fragment C2a. It also interacts with anticoagulant protein S and with serum amyloid P component. The beta chain binds protein S.
• KEGG Pathway:
  Complement and coagulation cascades (hsa04610)
  Pertussis (hsa05133)
• Reactome Pathway: Regulation of Complement cascade (R-HSA-977606)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial hypercholesterolemia	DISC06IX	Definitive	Genetic Variation	[1]
Hypercholesterolemia, familial, 1	DISU411W	Definitive	Genetic Variation	[1]
Non-small-cell lung cancer	DIS5Y6R9	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Amyloidosis	DISHTAI2	Strong	Biomarker	[4]
Autoimmune disease	DISORMTM	Strong	Biomarker	[5]
Behcet disease	DISSYMBS	Strong	Biomarker	[6]
Complement component 4a deficiency	DIS3JS22	Strong	Biomarker	[7]
Complement component 4b deficiency	DIS1ICRN	Strong	Genetic Variation	[7]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[3]
IgA nephropathy	DISZ8MTK	Strong	Biomarker	[7]
Protein S deficiency	DISORLOT	Strong	Genetic Variation	[8]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[9]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[10]
Pneumonia	DIS8EF3M	moderate	Altered Expression	[10]
Pulmonary tuberculosis	DIS6FLUM	moderate	Biomarker	[10]
Gonorrhea	DISQ5AO6	Limited	Biomarker	[11]
Neoplasm	DISZKGEW	Limited	Altered Expression	[12]

10 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 C4b-binding protein beta chain (C4BPB).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of C4b-binding protein beta chain (C4BPB).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of C4b-binding protein beta chain (C4BPB).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of C4b-binding protein beta chain (C4BPB).	[16]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of C4b-binding protein beta chain (C4BPB).	[14]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of C4b-binding protein beta chain (C4BPB).	[17]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of C4b-binding protein beta chain (C4BPB).	[18]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of C4b-binding protein beta chain (C4BPB).	[19]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of C4b-binding protein beta chain (C4BPB).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of C4b-binding protein beta chain (C4BPB).	[22]

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 increases the methylation of C4b-binding protein beta chain (C4BPB).	[21]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of C4b-binding protein beta chain (C4BPB).	[23]

References

• [1] Effects of LDL-apheresis on serum lipoprotein (a), C4b binding protein, protein C, protein S, and complement components.J Atheroscler Thromb. 1994;1(2):103-7. doi: 10.5551/jat1994.1.103.
• [2] Non-small cell lung cancer cells produce a functional set of complement factor I and its soluble cofactors.Mol Immunol. 2008 Jan;45(1):169-79. doi: 10.1016/j.molimm.2007.04.025. Epub 2007 Jun 4.
• [3] UPLC-MS/MS based diagnostics for epithelial ovarian cancer using fully sialylated C4-binding protein.Biomed Chromatogr. 2018 May;32(5):e4180. doi: 10.1002/bmc.4180. Epub 2018 Jan 23.
• [4] C4b-binding protein: The good, the bad and the deadly. Novel functions of an old friend.Immunol Lett. 2016 Jan;169:82-92. doi: 10.1016/j.imlet.2015.11.014. Epub 2015 Dec 2.
• [5] The 70 isoform of the complement regulator C4b-binding protein induces a semimature, anti-inflammatory state in dendritic cells.J Immunol. 2013 Mar 15;190(6):2857-72. doi: 10.4049/jimmunol.1200503. Epub 2013 Feb 6.
• [6] C4 binding protein deficiency in a patient with atypical Behet's disease.J Rheumatol. 1987 Feb;14(1):135-8.
• [7] Role for specific complement phenotypes and deficiencies in the clinical expression of IgA nephropathy.Am J Med Sci. 1991 Feb;301(2):115-23. doi: 10.1097/00000441-199102000-00006.
• [8] Lack of sequence variations in the C4b-BP beta-chain in patients with type III protein S deficiency bearing the Ser 460 to Pro mutation: description of two new intragenic isomorphisms in the C4b-BP beta-chain gene (C4BPB).Br J Haematol. 1998 Apr;101(1):10-5. doi: 10.1046/j.1365-2141.1998.00646.x.
• [9] Differential Intestinal Mucosa Transcriptomic Biomarkers for Crohn's Disease and Ulcerative Colitis.J Immunol Res. 2018 Oct 17;2018:9208274. doi: 10.1155/2018/9208274. eCollection 2018.
• [10] Serum amyloid A, protein Z, and C4b-binding protein chain as new potential biomarkers for pulmonary tuberculosis.PLoS One. 2017 Mar 9;12(3):e0173304. doi: 10.1371/journal.pone.0173304. eCollection 2017.
• [11] C4BP-IgM protein as a therapeutic approach to treat Neisseria gonorrhoeae infections.JCI Insight. 2019 Dec 5;4(23):e131886. doi: 10.1172/jci.insight.131886.
• [12] Regulation of complement classical pathway by association of C4b-binding protein to the surfaces of SK-OV-3 and Caov-3 ovarian adenocarcinoma cells.J Immunol. 2001 Jul 15;167(2):935-9. doi: 10.4049/jimmunol.167.2.935.
• [13] 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.
• [14] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [15] 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.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [18] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [19] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [20] A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer. Toxicol Appl Pharmacol. 2015 Jun 1;285(2):79-88.
• [21] 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.
• [22] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [23] 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.