Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCKR304)

• DOT Name: Complement component C6 (C6)
• Gene Name: C6
• Related Disease:
  Asthma
  Chronic renal failure
  Complement component 6 deficiency
  Complement deficiency
  End-stage renal disease
  Glomerulonephritis
  Haemophilia A
  Hepatocellular carcinoma
  Hyperthyroidism
  Influenza
  Meningococcal meningitis
  Nasal polyp
  Paroxysmal nocturnal haemoglobinuria
  Systemic lupus erythematosus
  Calcinosis
  Familial tumoral calcinosis
  Heart valve disorder
  Advanced cancer
  Arthritis
  Complement component 7 deficiency
• UniProt ID: CO6_HUMAN
• PDB ID: 3T5O; 4A5W; 4E0S; 6H03; 6H04; 7NYC; 7NYD; 7Q6C; 8B0F; 8B0G; 8B0H
• Pfam ID: PF21288 ; PF21195 ; PF00057 ; PF01823 ; PF00084 ; PF00090
• Sequence:
  MARRSVLYFILLNALINKGQACFCDHYAWTQWTSCSKTCNSGTQSRHRQIVVDKYYQENF
  CEQICSKQETRECNWQRCPINCLLGDFGPWSDCDPCIEKQSKVRSVLRPSQFGGQPCTAP
  LVAFQPCIPSKLCKIEEADCKNKFRCDSGRCIARKLECNGENDCGDNSDERDCGRTKAVC
  TRKYNPIPSVQLMGNGFHFLAGEPRGEVLDNSFTGGICKTVKSSRTSNPYRVPANLENVG
  FEVQTAEDDLKTDFYKDLTSLGHNENQQGSFSSQGGSSFSVPIFYSSKRSENINHNSAFK
  QAIQASHKKDSSFIRIHKVMKVLNFTTKAKDLHLSDVFLKALNHLPLEYNSALYSRIFDD
  FGTHYFTSGSLGGVYDLLYQFSSEELKNSGLTEEEAKHCVRIETKKRVLFAKKTKVEHRC
  TTNKLSEKHEGSFIQGAEKSISLIRGGRSEYGAALAWEKGSSGLEEKTFSEWLESVKENP
  AVIDFELAPIVDLVRNIPCAVTKRNNLRKALQEYAAKFDPCQCAPCPNNGRPTLSGTECL
  CVCQSGTYGENCEKQSPDYKSNAVDGQWGCWSSWSTCDATYKRSRTRECNNPAPQRGGKR
  CEGEKRQEEDCTFSIMENNGQPCINDDEEMKEVDLPEIEADSGCPQPVPPENGFIRNEKQ
  LYLVGEDVEISCLTGFETVGYQYFRCLPDGTWRQGDVECQRTECIKPVVQEVLTITPFQR
  LYRIGESIELTCPKGFVVAGPSRYTCQGNSWTPPISNSLTCEKDTLTKLKGHCQLGQKQS
  GSECICMSPEEDCSHHSEDLCVFDTDSNDYFTSPACKFLAEKCLNNQQLHFLHIGSCQDG
  RQLEWGLERTRLSSNSTKKESCGYDTCYDWEKCSASTSKCVCLLPPQCFKGGNQLYCVKM
  GSSTSEKTLNICEVGTIRCANRKMEILHPGKCLA
• Function: Constituent of the membrane attack complex (MAC) that plays a key role in the innate and adaptive immune response by forming pores in the plasma membrane of target cells.
• KEGG Pathway:
  Complement and coagulation cascades (hsa04610)
  Regulation of actin cytoskeleton (hsa04810)
  Prion disease (hsa05020)
  Coro.virus disease - COVID-19 (hsa05171)
  Systemic lupus erythematosus (hsa05322)
• Reactome Pathway:
  Regulation of Complement cascade (R-HSA-977606)
  Terminal pathway of complement (R-HSA-166665)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Asthma	DISW9QNS	Strong	Genetic Variation	[1]
Chronic renal failure	DISGG7K6	Strong	ModifyingMutation	[2]
Complement component 6 deficiency	DISY31NP	Strong	Autosomal recessive	[3]
Complement deficiency	DISGN469	Strong	Biomarker	[4]
End-stage renal disease	DISXA7GG	Strong	ModifyingMutation	[2]
Glomerulonephritis	DISPZIQ3	Strong	Biomarker	[5]
Haemophilia A	DIS0RQ2E	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[7]
Hyperthyroidism	DISX87ZH	Strong	Genetic Variation	[8]
Influenza	DIS3PNU3	Strong	Altered Expression	[9]
Meningococcal meningitis	DISCKTAT	Strong	Genetic Variation	[10]
Nasal polyp	DISLP3XE	Strong	Biomarker	[1]
Paroxysmal nocturnal haemoglobinuria	DISBHMYH	Strong	Altered Expression	[9]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[8]
Calcinosis	DISQP4OR	moderate	Biomarker	[11]
Familial tumoral calcinosis	DISYJZKG	moderate	Biomarker	[11]
Heart valve disorder	DIS84O7T	moderate	Biomarker	[11]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[12]
Arthritis	DIST1YEL	Limited	Biomarker	[13]
Complement component 7 deficiency	DIST3K9E	Limited	Biomarker	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Complement component C6 (C6).	[15]
Olanzapine	DMPFN6Y	Approved	Olanzapine affects the phosphorylation of Complement component C6 (C6).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Complement component C6 (C6).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Complement component C6 (C6).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Complement component C6 (C6).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Complement component C6 (C6).	[18]

References

• [1] Association analysis of C6 genetic variations and aspirin hypersensitivity in Korean asthmatic patients.Hum Immunol. 2011 Oct;72(10):973-8. doi: 10.1016/j.humimm.2011.05.022. Epub 2011 Jun 7.
• [2] C6 mediates chronic progression of tubulointerstitial damage in rats with remnant kidneys.J Am Soc Nephrol. 2002 Apr;13(4):928-936. doi: 10.1681/ASN.V134928.
• [3] Prevalence of mutations leading to complete C6 deficiency (C6Q0) in the Western Cape, South Africa and detection of novel mutations leading to C6Q0 in an Irish family. Mol Immunol. 2007 Apr;44(10):2756-60. doi: 10.1016/j.molimm.2006.11.022. Epub 2007 Jan 25.
• [4] Restricted genetic defects underlie human complement C6 deficiency.Clin Exp Immunol. 2003 Apr;132(1):87-91. doi: 10.1046/j.1365-2249.2003.02099.x.
• [5] C5b-9 membrane attack complex mediates endothelial cell apoptosis in experimental glomerulonephritis.Am J Physiol Renal Physiol. 2000 May;278(5):F747-57. doi: 10.1152/ajprenal.2000.278.5.F747.
• [6] Combined hereditary deficiency of the sixth component of complement and factor VIII coagulant activity in a Dutch family.Clin Exp Immunol. 1982 Jun;48(3):733-8.
• [7] Gene Variations of Sixth Complement Component Affecting Tacrolimus Metabolism in Patients with Liver Transplantation for Hepatocellular Carcinoma.Chin Med J (Engl). 2017 Jul 20;130(14):1670-1676. doi: 10.4103/0366-6999.209886.
• [8] Hereditary complement (C6) deficiency associated with systemic lupus erythematosus, Sjgren's syndrome and hyperthyroidism.J Rheumatol. 1987 Oct;14(5):1030-3.
• [9] Hereditary deficiency of the sixth component of complement in man. I. Immunochemical, biologic, and family studies.J Clin Invest. 1974 Feb;53(2):544-53. doi: 10.1172/JCI107588.
• [10] Complement component C6 deficiency in a Spanish family: implications for clinical and molecular diagnosis.Gene. 2013 May 25;521(1):204-6. doi: 10.1016/j.gene.2013.03.027. Epub 2013 Mar 26.
• [11] Raloxifene attenuates Gas6 and apoptosis in experimental aortic valve disease in renal failure.Am J Physiol Heart Circ Physiol. 2011 May;300(5):H1829-40. doi: 10.1152/ajpheart.00240.2010. Epub 2011 Feb 18.
• [12] Recipient C6 rs9200 genotype is associated with hepatocellular carcinoma recurrence after orthotopic liver transplantation in a Han Chinese population.Cancer Gene Ther. 2016 Jun;23(6):157-61. doi: 10.1038/cgt.2016.7. Epub 2016 May 13.
• [13] Arthritis and antinuclear antibodies (ANA) with inherited deficiency of the sixth component of complement (C6).Ann Rheum Dis. 1986 May;45(5):431-4. doi: 10.1136/ard.45.5.431.
• [14] Diagnosis of primary antibody and complement deficiencies in young adults after a first invasive bacterial infection.Clin Microbiol Infect. 2017 Aug;23(8):576.e1-576.e5. doi: 10.1016/j.cmi.2017.02.005. Epub 2017 Feb 10.
• [15] 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.
• [16] 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.
• [17] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [18] 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.
• [19] 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.
• [20] 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.