Details of Drug Off-Target (DOT)

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

• DOT Name: Complement C4-A (C4A)
• Synonyms: Acidic complement C4; C3 and PZP-like alpha-2-macroglobulin domain-containing protein 2
• Gene Name: C4A
• Related Disease:
  Chronic kidney disease
  Acute myocardial infarction
  Anterior uveitis
  Asthma
  Autoimmune hepatitis
  Autosomal systemic lupus erythematosus type 16
  Behcet disease
  Burkitt lymphoma
  Chronic obstructive pulmonary disease
  Complement component 2 deficiency
  Complement component 4a deficiency
  Complement component 4b deficiency
  Complement deficiency
  Crohn disease
  Cyclic hematopoiesis
  Graves disease
  Juvenile idiopathic arthritis
  Primary biliary cholangitis
  Rheumatic heart disease
  Rheumatoid arthritis
  Schizophrenia
  Sjogren syndrome
  Subacute cutaneous lupus erythematosus
  Type-1 diabetes
  Ulcerative colitis
  Age-related macular degeneration
  Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
  Immune system disorder
  Type-1/2 diabetes
  Autoimmune disease
  Immunodeficiency
  Myasthenia gravis
  Non-insulin dependent diabetes
  Parkinson disease
• UniProt ID: CO4A_HUMAN
• PDB ID: 1HZF; 5JPM; 5JPN; 5JTW; 6YSQ
• Pfam ID: PF00207 ; PF07703 ; PF07677 ; PF01821 ; PF21145 ; PF01835 ; PF17791 ; PF17789 ; PF01759 ; PF07678
• Sequence:
  MRLLWGLIWASSFFTLSLQKPRLLLFSPSVVHLGVPLSVGVQLQDVPRGQVVKGSVFLRN
  PSRNNVPCSPKVDFTLSSERDFALLSLQVPLKDAKSCGLHQLLRGPEVQLVAHSPWLKDS
  LSRTTNIQGINLLFSSRRGHLFLQTDQPIYNPGQRVRYRVFALDQKMRPSTDTITVMVEN
  SHGLRVRKKEVYMPSSIFQDDFVIPDISEPGTWKISARFSDGLESNSSTQFEVKKYVLPN
  FEVKITPGKPYILTVPGHLDEMQLDIQARYIYGKPVQGVAYVRFGLLDEDGKKTFFRGLE
  SQTKLVNGQSHISLSKAEFQDALEKLNMGITDLQGLRLYVAAAIIESPGGEMEEAELTSW
  YFVSSPFSLDLSKTKRHLVPGAPFLLQALVREMSGSPASGIPVKVSATVSSPGSVPEVQD
  IQQNTDGSGQVSIPIIIPQTISELQLSVSAGSPHPAIARLTVAAPPSGGPGFLSIERPDS
  RPPRVGDTLNLNLRAVGSGATFSHYYYMILSRGQIVFMNREPKRTLTSVSVFVDHHLAPS
  FYFVAFYYHGDHPVANSLRVDVQAGACEGKLELSVDGAKQYRNGESVKLHLETDSLALVA
  LGALDTALYAAGSKSHKPLNMGKVFEAMNSYDLGCGPGGGDSALQVFQAAGLAFSDGDQW
  TLSRKRLSCPKEKTTRKKRNVNFQKAINEKLGQYASPTAKRCCQDGVTRLPMMRSCEQRA
  ARVQQPDCREPFLSCCQFAESLRKKSRDKGQAGLQRALEILQEEDLIDEDDIPVRSFFPE
  NWLWRVETVDRFQILTLWLPDSLTTWEIHGLSLSKTKGLCVATPVQLRVFREFHLHLRLP
  MSVRRFEQLELRPVLYNYLDKNLTVSVHVSPVEGLCLAGGGGLAQQVLVPAGSARPVAFS
  VVPTAAAAVSLKVVARGSFEFPVGDAVSKVLQIEKEGAIHREELVYELNPLDHRGRTLEI
  PGNSDPNMIPDGDFNSYVRVTASDPLDTLGSEGALSPGGVASLLRLPRGCGEQTMIYLAP
  TLAASRYLDKTEQWSTLPPETKDHAVDLIQKGYMRIQQFRKADGSYAAWLSRDSSTWLTA
  FVLKVLSLAQEQVGGSPEKLQETSNWLLSQQQADGSFQDPCPVLDRSMQGGLVGNDETVA
  LTAFVTIALHHGLAVFQDEGAEPLKQRVEASISKANSFLGEKASAGLLGAHAAAITAYAL
  TLTKAPVDLLGVAHNNLMAMAQETGDNLYWGSVTGSQSNAVSPTPAPRNPSDPMPQAPAL
  WIETTAYALLHLLLHEGKAEMADQASAWLTRQGSFQGGFRSTQDTVIALDALSAYWIASH
  TTEERGLNVTLSSTGRNGFKSHALQLNNRQIRGLEEELQFSLGSKINVKVGGNSKGTLKV
  LRTYNVLDMKNTTCQDLQIEVTVKGHVEYTMEANEDYEDYEYDELPAKDDPDAPLQPVTP
  LQLFEGRRNRRRREAPKVVEEQESRVHYTVCIWRNGKVGLSGMAIADVTLLSGFHALRAD
  LEKLTSLSDRYVSHFETEGPHVLLYFDSVPTSRECVGFEAVQEVPVGLVQPASATLYDYY
  NPERRCSVFYGAPSKSRLLATLCSAEVCQCAEGKCPRQRRALERGLQDEDGYRMKFACYY
  PRVEYGFQVKVLREDSRAAFRLFETKITQVLHFTKDVKAAANQMRNFLVRASCRLRLEPG
  KEYLIMGLDGATYDLEGHPQYLLDSNSWIEEMPSERLCRSTRQRAACAQLNDFLQEYGTQ
  GCQV
• Function: Non-enzymatic component of C3 and C5 convertases and thus essential for the propagation of the classical complement pathway. Covalently binds to immunoglobulins and immune complexes and enhances the solubilization of immune aggregates and the clearance of IC through CR1 on erythrocytes. C4A isotype is responsible for effective binding to form amide bonds with immune aggregates or protein antigens, while C4B isotype catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens.; Derived from proteolytic degradation of complement C4, C4a anaphylatoxin is a mediator of local inflammatory process. It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes.
• Tissue Specificity: Complement component C4 is expressed at highest levels in the liver, at moderate levels in the adrenal cortex, adrenal medulla, thyroid gland, and the kidney, and at lowest levels in the heart, ovary, small intestine, thymus, pancreas and spleen. The extra-hepatic sites of expression may be important for the local protection and inflammatory response.
• KEGG Pathway:
  Complement and coagulation cascades (hsa04610)
  Alcoholic liver disease (hsa04936)
  Pertussis (hsa05133)
  Staphylococcus aureus infection (hsa05150)
  Coro.virus disease - COVID-19 (hsa05171)
  Systemic lupus erythematosus (hsa05322)
• Reactome Pathway:
  Activation of C3 and C5 (R-HSA-174577)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Post-translational protein phosphorylation (R-HSA-8957275)
  Regulation of Complement cascade (R-HSA-977606)
  Initial triggering of complement (R-HSA-166663)

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic kidney disease	DISW82R7	Definitive	Biomarker	[1]
Acute myocardial infarction	DISE3HTG	Strong	Genetic Variation	[2]
Anterior uveitis	DISQ7EAD	Strong	Biomarker	[3]
Asthma	DISW9QNS	Strong	Altered Expression	[4]
Autoimmune hepatitis	DISOX03Q	Strong	Genetic Variation	[5]
Autosomal systemic lupus erythematosus type 16	DIS9RKY9	Strong	SusceptibilityMutation	[6]
Behcet disease	DISSYMBS	Strong	SusceptibilityMutation	[7]
Burkitt lymphoma	DIS9D5XU	Strong	Biomarker	[8]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Altered Expression	[4]
Complement component 2 deficiency	DIS8OWGU	Strong	Genetic Variation	[9]
Complement component 4a deficiency	DIS3JS22	Strong	Autosomal recessive	[10]
Complement component 4b deficiency	DIS1ICRN	Strong	Autosomal recessive	[11]
Complement deficiency	DISGN469	Strong	Biomarker	[12]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[13]
Cyclic hematopoiesis	DISQQOM4	Strong	Biomarker	[14]
Graves disease	DISU4KOQ	Strong	Genetic Variation	[15]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[16]
Primary biliary cholangitis	DIS43E0O	Strong	Biomarker	[17]
Rheumatic heart disease	DISCI8JQ	Strong	Biomarker	[18]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[19]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[20]
Sjogren syndrome	DISUBX7H	Strong	Genetic Variation	[21]
Subacute cutaneous lupus erythematosus	DIS6XDK0	Strong	Genetic Variation	[21]
Type-1 diabetes	DIS7HLUB	Strong	Biomarker	[22]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[13]
Age-related macular degeneration	DIS0XS2C	moderate	Genetic Variation	[23]
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	DISMTRY0	moderate	Genetic Variation	[24]
Immune system disorder	DISAEGPH	moderate	Biomarker	[25]
Type-1/2 diabetes	DISIUHAP	moderate	Biomarker	[26]
Autoimmune disease	DISORMTM	Limited	Biomarker	[27]
Immunodeficiency	DIS093I0	Limited	Biomarker	[28]
Myasthenia gravis	DISELRCI	Limited	Genetic Variation	[29]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[30]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Complement C4-A (C4A).	[32]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Complement C4-A (C4A).	[33]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Complement C4-A (C4A).	[34]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Complement C4-A (C4A).	[35]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of Complement C4-A (C4A).	[36]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Complement C4-A (C4A).	[38]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Complement C4-A (C4A).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Olanzapine	DMPFN6Y	Approved	Olanzapine decreases the phosphorylation of Complement C4-A (C4A).	[37]

References

• [1] C4A deficiency and poor prognosis in patients with IgA nephropathy.Clin Nephrol. 1991 Jul;36(1):1-5.
• [2] Low complement C4B gene copy number predicts short-term mortality after acute myocardial infarction.Int Immunol. 2008 Jan;20(1):31-7. doi: 10.1093/intimm/dxm117. Epub 2007 Nov 20.
• [3] Association of complement allotype C4B2 with anterior uveitis.Hum Immunol. 1988 Apr;21(4):233-7. doi: 10.1016/0198-8859(88)90032-8.
• [4] Complement factors c3a, c4a, and c5a in chronic obstructive pulmonary disease and asthma.Am J Respir Cell Mol Biol. 2004 Aug;31(2):216-9. doi: 10.1165/rcmb.2003-0394OC. Epub 2004 Mar 23.
• [5] Early-onset autoimmune hepatitis is associated with a C4A gene deletion.Gastroenterology. 1993 May;104(5):1478-84. doi: 10.1016/0016-5085(93)90359-k.
• [6] The role of complement in the development of systemic lupus erythematosus.Annu Rev Immunol. 2004;22:431-56. doi: 10.1146/annurev.immunol.22.012703.104549.
• [7] Copy number variations of complement component C4 are associated with Behet's disease but not with ankylosing spondylitis associated with acute anterior uveitis.Arthritis Rheum. 2013 Nov;65(11):2963-70. doi: 10.1002/art.38116.
• [8] The 5' regulatory sequences of active miR-146a promoters are hypomethylated and associated with euchromatic histone modification marks in B lymphoid cells.Biochem Biophys Res Commun. 2013 Apr 19;433(4):489-95. doi: 10.1016/j.bbrc.2013.03.022. Epub 2013 Mar 23.
• [9] Type I human complement C2 deficiency. A 28-base pair gene deletion causes skipping of exon 6 during RNA splicing. J Biol Chem. 1992 May 5;267(13):9347-53.
• [10] Complete complement components C4A and C4B deficiencies in human kidney diseases and systemic lupus erythematosus. J Immunol. 2004 Aug 15;173(4):2803-14. doi: 10.4049/jimmunol.173.4.2803.
• [11] Deficiency of human complement protein C4 due to identical frameshift mutations in the C4A and C4B genes. J Immunol. 1999 Mar 15;162(6):3687-93.
• [12] Complement-4 deficiency in a child with systemic lupus erythematosus presenting with standard treatment-resistant severe skin lesion.ISRN Rheumatol. 2011;2011:917673. doi: 10.5402/2011/917673. Epub 2011 Feb 10.
• [13] Novel Associations Between Major Histocompatibility Complex and Pediatric-onset Inflammatory Bowel Disease.J Pediatr Gastroenterol Nutr. 2016 Apr;62(4):567-72. doi: 10.1097/MPG.0000000000000984.
• [14] C4B3 allotype with a novel Ch phenotype.Immunogenetics. 1985;22(6):609-16. doi: 10.1007/BF00430309.
• [15] C4A gene deletion: association with Graves' disease.J Mol Endocrinol. 1989 Sep;3(2):145-53. doi: 10.1677/jme.0.0030145.
• [16] Partial C4 deficiency in juvenile idiopathic arthritis patients.J Clin Rheumatol. 2007 Oct;13(5):256-60. doi: 10.1097/RHU.0b013e318156b9e3.
• [17] Defining the immunogenetic susceptibility to primary biliary cirrhosis.Hepatology. 1994 Nov;20(5):1213-9.
• [18] Increased frequency of the C4A*6 rare allele in rheumatic heart disease.Scand J Rheumatol. 1995;24(3):164-8. doi: 10.3109/03009749509099307.
• [19] Properdin factor B and complement factor C4 allotypes in rheumatoid arthritis: results of a follow-up study.Hum Immunol. 1992 Feb;33(2):148-51. doi: 10.1016/0198-8859(92)90066-v.
• [20] Neuropil contraction in relation to Complement C4 gene copy numbers in independent cohorts of adolescent-onset and young adult-onset schizophrenia patients-a pilot study.Transl Psychiatry. 2018 Jul 19;8(1):134. doi: 10.1038/s41398-018-0181-z.
• [21] Clinical expression of systemic lupus erythematosus in patients with C4A deficiency.Medicine (Baltimore). 1993 Jul;72(4):236-44. doi: 10.1097/00005792-199307000-00003.
• [22] C4 Chido 3 and 6 distinguish two diabetogenic haplotypes: HLA-B49, SC01,DR4,DQw8 and B8,SC01,DR3,DQw2.Immunobiology. 1991 Sep;183(1-2):12-22. doi: 10.1016/S0171-2985(11)80182-8.
• [23] Multiallelic copy number variation in the complement component 4A (C4A) gene is associated with late-stage age-related macular degeneration (AMD).J Neuroinflammation. 2016 Apr 18;13(1):81. doi: 10.1186/s12974-016-0548-0.
• [24] The immunological detection of a 21-OH deficiency mutation HLA supratype.Am J Hum Genet. 1986 May;38(5):688-98.
• [25] Differences in the metabolism of C4 isotypes in patients with complement activation.Clin Exp Immunol. 1989 Oct;78(1):49-53.
• [26] Does a central MHC gene in linkage disequilibrium with HLA-DRB1*0401 affect susceptibility to type 1 diabetes?.Genes Immun. 2005 Jun;6(4):298-304. doi: 10.1038/sj.gene.6364210.
• [27] Association of three systemic lupus erythematosus susceptibility factors, PD-1.3A, C4AQ0, and low levels of mannan-binding lectin, with autoimmune manifestations in Icelandic multicase systemic lupus erythematosus families.Arthritis Rheum. 2008 Dec;58(12):3865-72. doi: 10.1002/art.24129.
• [28] Genetic basis of human complement C4A deficiency. Detection of a point mutation leading to nonexpression.J Clin Invest. 1993 Apr;91(4):1681-6. doi: 10.1172/JCI116377.
• [29] Ancestral haplotypes carry haplotypic and haplospecific polymorphisms of BAT1: possible relevance to autoimmune disease.Eur J Immunogenet. 1992 Jun;19(3):121-7. doi: 10.1111/j.1744-313x.1992.tb00051.x.
• [30] HLA, complement C2, C4, properdin factor B and glyoxalase types in South Indian diabetics.Diabetes Res Clin Pract. 1985 Mar;1(1):41-7. doi: 10.1016/s0168-8227(85)80027-9.
• [31] HLA-linked complement markers in Alzheimer's and Parkinson's disease: C4 variant (C4B2) a possible marker for senile dementia of the Alzheimer type.Neurology. 1984 Mar;34(3):310-4. doi: 10.1212/wnl.34.3.310.
• [32] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [33] 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.
• [34] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [35] A comprehensive analysis of Wnt/beta-catenin signaling pathway-related genes and crosstalk pathways in the treatment of As2O3 in renal cancer. Ren Fail. 2018 Nov;40(1):331-339.
• [36] 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.
• [37] 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.
• [38] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [39] Global gene expression analysis reveals novel transcription factors associated with long-term low-level exposure of EA.hy926 human endothelial cells to bisphenol A. Chem Biol Interact. 2023 Aug 25;381:110571. doi: 10.1016/j.cbi.2023.110571. Epub 2023 May 25.