Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQYYX0P)

• DOT Name: Complement factor I (CFI)
• Synonyms: EC 3.4.21.45; C3B/C4B inactivator
• Gene Name: CFI
• Related Disease:
  Atypical hemolytic uremic syndrome
  Atypical hemolytic-uremic syndrome with I factor anomaly
  Complement factor I deficiency
  Doyne honeycomb retinal dystrophy
  Age related macular degeneration 13
• UniProt ID: CFAI_HUMAN
• PDB ID: 2XRC; 5O32
• EC Number: 3.4.21.45
• Pfam ID: PF21286 ; PF21287 ; PF00057 ; PF00530 ; PF00089
• Sequence:
  MKLLHVFLLFLCFHLRFCKVTYTSQEDLVEKKCLAKKYTHLSCDKVFCQPWQRCIEGTCV
  CKLPYQCPKNGTAVCATNRRSFPTYCQQKSLECLHPGTKFLNNGTCTAEGKFSVSLKHGN
  TDSEGIVEVKLVDQDKTMFICKSSWSMREANVACLDLGFQQGADTQRRFKLSDLSINSTE
  CLHVHCRGLETSLAECTFTKRRTMGYQDFADVVCYTQKADSPMDDFFQCVNGKYISQMKA
  CDGINDCGDQSDELCCKACQGKGFHCKSGVCIPSQYQCNGEVDCITGEDEVGCAGFASVT
  QEETEILTADMDAERRRIKSLLPKLSCGVKNRMHIRRKRIVGGKRAQLGDLPWQVAIKDA
  SGITCGGIYIGGCWILTAAHCLRASKTHRYQIWTTVVDWIHPDLKRIVIEYVDRIIFHEN
  YNAGTYQNDIALIEMKKDGNKKDCELPRSIPACVPWSPYLFQPNDTCIVSGWGREKDNER
  VFSLQWGEVKLISNCSKFYGNRFYEKEMECAGTYDGSIDACKGDSGGPLVCMDANNVTYV
  WGVVSWGENCGKPEFPGVYTKVANYFDWISYHVGRPFISQYNV
• Function: Trypsin-like serine protease that plays an essential role in regulating the immune response by controlling all complement pathways. Inhibits these pathways by cleaving three peptide bonds in the alpha-chain of C3b and two bonds in the alpha-chain of C4b thereby inactivating these proteins. Essential cofactors for these reactions include factor H and C4BP in the fluid phase and membrane cofactor protein/CD46 and CR1 on cell surfaces. The presence of these cofactors on healthy cells allows degradation of deposited C3b by CFI in order to prevent undesired complement activation, while in apoptotic cells or microbes, the absence of such cofactors leads to C3b-mediated complement activation and subsequent opsonization.
• Tissue Specificity: Expressed in the liver by hepatocytes . Also present in other cells such as monocytes, fibroblasts or keratinocytes .
• KEGG Pathway:
  Complement and coagulation cascades (hsa04610)
  Staphylococcus aureus infection (hsa05150)
• Reactome Pathway: Regulation of Complement cascade (R-HSA-977606)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atypical hemolytic uremic syndrome	DIS6FUDJ	Definitive	Autosomal dominant	[1]
Atypical hemolytic-uremic syndrome with I factor anomaly	DIS5W0HW	Strong	Autosomal dominant	[2]
Complement factor I deficiency	DISW8HB5	Strong	Autosomal recessive	[3]
Doyne honeycomb retinal dystrophy	DISKFNCT	Supportive	Autosomal dominant	[4]
Age related macular degeneration 13	DISSMEV1	Limited	Autosomal dominant	[5]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cyclophosphamide	DM4O2Z7	Approved	Complement factor I (CFI) affects the response to substance of Cyclophosphamide.	[23]

16 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 I (CFI).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Complement factor I (CFI).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Complement factor I (CFI).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Complement factor I (CFI).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Complement factor I (CFI).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Complement factor I (CFI).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Complement factor I (CFI).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Complement factor I (CFI).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Complement factor I (CFI).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Complement factor I (CFI).	[15]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Complement factor I (CFI).	[16]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of Complement factor I (CFI).	[17]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Complement factor I (CFI).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Complement factor I (CFI).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Complement factor I (CFI).	[21]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Complement factor I (CFI).	[22]

1 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 decreases the methylation of Complement factor I (CFI).	[19]

References

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• [2] Mutations in complement factor I predispose to development of atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2005 Jul;16(7):2150-5. doi: 10.1681/ASN.2005010103. Epub 2005 May 25.
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• [4] Rare genetic variants in Tunisian Jewish patients suffering from age-related macular degeneration. J Med Genet. 2015 Jul;52(7):484-92. doi: 10.1136/jmedgenet-2015-103130. Epub 2015 May 18.
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• [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.
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• [22] 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.
• [23] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.