Details of Drug Off-Target (DOT)

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

• DOT Name: Complement factor B (CFB)
• Synonyms: EC 3.4.21.47; C3/C5 convertase; Glycine-rich beta glycoprotein; GBG; PBF2; Properdin factor B
• Gene Name: CFB
• Related Disease:
  Atypical hemolytic-uremic syndrome with B factor anomaly
  Complement factor b deficiency
• UniProt ID: CFAB_HUMAN
• PDB ID: 1DLE; 1Q0P; 1RRK; 1RS0; 1RTK; 2OK5; 2WIN; 2XWB; 2XWJ; 3HRZ; 3HS0; 6QSW; 6QSX; 6RAV; 6RUR; 6RUV; 6T8U; 6T8V; 6T8W; 7JTN; 7JTQ; 7NOZ; 8ENU; 8EOK
• EC Number: 3.4.21.47
• Pfam ID: PF00084 ; PF00089 ; PF00092
• Sequence:
  MGSNLSPQLCLMPFILGLLSGGVTTTPWSLARPQGSCSLEGVEIKGGSFRLLQEGQALEY
  VCPSGFYPYPVQTRTCRSTGSWSTLKTQDQKTVRKAECRAIHCPRPHDFENGEYWPRSPY
  YNVSDEISFHCYDGYTLRGSANRTCQVNGRWSGQTAICDNGAGYCSNPGIPIGTRKVGSQ
  YRLEDSVTYHCSRGLTLRGSQRRTCQEGGSWSGTEPSCQDSFMYDTPQEVAEAFLSSLTE
  TIEGVDAEDGHGPGEQQKRKIVLDPSGSMNIYLVLDGSDSIGASNFTGAKKCLVNLIEKV
  ASYGVKPRYGLVTYATYPKIWVKVSEADSSNADWVTKQLNEINYEDHKLKSGTNTKKALQ
  AVYSMMSWPDDVPPEGWNRTRHVIILMTDGLHNMGGDPITVIDEIRDLLYIGKDRKNPRE
  DYLDVYVFGVGPLVNQVNINALASKKDNEQHVFKVKDMENLEDVFYQMIDESQSLSLCGM
  VWEHRKGTDYHKQPWQAKISVIRPSKGHESCMGAVVSEYFVLTAAHCFTVDDKEHSIKVS
  VGGEKRDLEIEVVLFHPNYNINGKKEAGIPEFYDYDVALIKLKNKLKYGQTIRPICLPCT
  EGTTRALRLPPTTTCQQQKEELLPAQDIKALFVSEEEKKLTRKEVYIKNGDKKGSCERDA
  QYAPGYDKVKDISEVVTPRFLCTGGVSPYADPNTCRGDSGGPLIVHKRSRFIQVGVISWG
  VVDVCKNQKRQKQVPAHARDFHINLFQVLPWLKEKLQDEDLGFL
• Function: Factor B which is part of the alternate pathway of the complement system is cleaved by factor D into 2 fragments: Ba and Bb. Bb, a serine protease, then combines with complement factor 3b to generate the C3 or C5 convertase. It has also been implicated in proliferation and differentiation of preactivated B-lymphocytes, rapid spreading of peripheral blood monocytes, stimulation of lymphocyte blastogenesis and lysis of erythrocytes. Ba inhibits the proliferation of preactivated B-lymphocytes.
• KEGG Pathway:
  Complement and coagulation cascades (hsa04610)
  Staphylococcus aureus infection (hsa05150)
  Coro.virus disease - COVID-19 (hsa05171)
• Reactome Pathway:
  Activation of C3 and C5 (R-HSA-174577)
  Regulation of Complement cascade (R-HSA-977606)
  Alternative complement activation (R-HSA-173736)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atypical hemolytic-uremic syndrome with B factor anomaly	DISZ9IGZ	Strong	Autosomal dominant	[1]
Complement factor b deficiency	DISN5T3L	Moderate	Autosomal recessive	[2]

19 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 Complement factor B (CFB).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Complement factor B (CFB).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Complement factor B (CFB).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Complement factor B (CFB).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Complement factor B (CFB).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Complement factor B (CFB).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Complement factor B (CFB).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Complement factor B (CFB).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Complement factor B (CFB).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Complement factor B (CFB).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Complement factor B (CFB).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Complement factor B (CFB).	[13]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Complement factor B (CFB).	[14]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Complement factor B (CFB).	[15]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Complement factor B (CFB).	[16]
Danazol	DML8KTN	Approved	Danazol increases the expression of Complement factor B (CFB).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Complement factor B (CFB).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Complement factor B (CFB).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Complement factor B (CFB).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Olanzapine	DMPFN6Y	Approved	Olanzapine affects the phosphorylation of Complement factor B (CFB).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Complement factor B (CFB).	[19]

References

• [1] Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):240-5. doi: 10.1073/pnas.0603420103. Epub 2006 Dec 20.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [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] 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.
• [5] Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
• [6] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [12] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [13] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [14] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [15] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [16] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [17] Effects of olanzapine on serum protein phosphorylation patterns in patients with schizophrenia. Proteomics Clin Appl. 2015 Oct;9(9-10):907-16. doi: 10.1002/prca.201400148. Epub 2015 May 15.
• [18] Guillain-Barr syndrome following danazol and corticosteroid therapy for hereditary angioedema. Am J Med. 1985 Jul;79(1):111-4. doi: 10.1016/0002-9343(85)90553-4.
• [19] 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.
• [20] Genome-wide gene expression profiling of low-dose, long-term exposure of human osteosarcoma cells to bisphenol A and its analogs bisphenols AF and S. Toxicol In Vitro. 2015 Aug;29(5):1060-9.
• [21] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.