Details of Drug Off-Target (DOT)

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

• DOT Name: Complement factor H (CFH)
• Synonyms: H factor 1
• Gene Name: CFH
• Related Disease:
  Atypical hemolytic uremic syndrome
  Primary membranoproliferative glomerulonephritis
  Basal laminar drusen
  Complement factor H deficiency
  Hemolytic uremic syndrome, atypical, susceptibility to, 1
  Dense deposit disease
  Doyne honeycomb retinal dystrophy
• UniProt ID: CFAH_HUMAN
• PDB ID: 1HAQ ; 1HCC ; 1HFH ; 1HFI ; 2BZM ; 2G7I ; 2IC4 ; 2JGW ; 2JGX ; 2KMS ; 2QFG ; 2QFH ; 2RLP ; 2RLQ ; 2UWN ; 2V8E ; 2W80 ; 2W81 ; 2WII ; 2XQW ; 3GAU ; 3GAV ; 3GAW ; 3KXV ; 3KZJ ; 3OXU ; 3R62 ; 3RJ3 ; 3SW0 ; 4AYD ; 4AYE ; 4AYI ; 4AYM ; 4B2R ; 4B2S ; 4J38 ; 4K12 ; 4ONT ; 4ZH1 ; 5NBQ ; 5O32 ; 5O35 ; 5WTB ; 6ATG ; 6ZH1 ; 7WKI ; 7ZJM
• Pfam ID: PF00084
• Sequence:
  MRLLAKIICLMLWAICVAEDCNELPPRRNTEILTGSWSDQTYPEGTQAIYKCRPGYRSLG
  NVIMVCRKGEWVALNPLRKCQKRPCGHPGDTPFGTFTLTGGNVFEYGVKAVYTCNEGYQL
  LGEINYRECDTDGWTNDIPICEVVKCLPVTAPENGKIVSSAMEPDREYHFGQAVRFVCNS
  GYKIEGDEEMHCSDDGFWSKEKPKCVEISCKSPDVINGSPISQKIIYKENERFQYKCNMG
  YEYSERGDAVCTESGWRPLPSCEEKSCDNPYIPNGDYSPLRIKHRTGDEITYQCRNGFYP
  ATRGNTAKCTSTGWIPAPRCTLKPCDYPDIKHGGLYHENMRRPYFPVAVGKYYSYYCDEH
  FETPSGSYWDHIHCTQDGWSPAVPCLRKCYFPYLENGYNQNYGRKFVQGKSIDVACHPGY
  ALPKAQTTVTCMENGWSPTPRCIRVKTCSKSSIDIENGFISESQYTYALKEKAKYQCKLG
  YVTADGETSGSITCGKDGWSAQPTCIKSCDIPVFMNARTKNDFTWFKLNDTLDYECHDGY
  ESNTGSTTGSIVCGYNGWSDLPICYERECELPKIDVHLVPDRKKDQYKVGEVLKFSCKPG
  FTIVGPNSVQCYHFGLSPDLPICKEQVQSCGPPPELLNGNVKEKTKEEYGHSEVVEYYCN
  PRFLMKGPNKIQCVDGEWTTLPVCIVEESTCGDIPELEHGWAQLSSPPYYYGDSVEFNCS
  ESFTMIGHRSITCIHGVWTQLPQCVAIDKLKKCKSSNLIILEEHLKNKKEFDHNSNIRYR
  CRGKEGWIHTVCINGRWDPEVNCSMAQIQLCPPPPQIPNSHNMTTTLNYRDGEKVSVLCQ
  ENYLIQEGEEITCKDGRWQSIPLCVEKIPCSQPPQIEHGTINSSRSSQESYAHGTKLSYT
  CEGGFRISEENETTCYMGKWSSPPQCEGLPCKSPPEISHGVVAHMSDSYQYGEEVTYKCF
  EGFGIDGPAIAKCLGEKWSHPPSCIKTDCLSLPSFENAIPMGEKKDVYKAGEQVTYTCAT
  YYKMDGASNVTCINSRWTGRPTCRDTSCVNPPTVQNAYIVSRQMSKYPSGERVRYQCRSP
  YEMFGDEEVMCLNGNWTEPPQCKDSTGKCGPPPPIDNGDITSFPLSVYAPASSVEYQCQN
  LYQLEGNKRITCRNGQWSEPPKCLHPCVISREIMENYNIALRWTAKQKLYSRTGESVEFV
  CKRGYRLSSRSHTLRTTCWDGKLEYPTCAKR
• Function: Glycoprotein that plays an essential role in maintaining a well-balanced immune response by modulating complement activation. Acts as a soluble inhibitor of complement, where its binding to self markers such as glycan structures prevents complement activation and amplification on cell surfaces. Accelerates the decay of the complement alternative pathway (AP) C3 convertase C3bBb, thus preventing local formation of more C3b, the central player of the complement amplification loop. As a cofactor of the serine protease factor I, CFH also regulates proteolytic degradation of already-deposited C3b. In addition, mediates several cellular responses through interaction with specific receptors. For example, interacts with CR3/ITGAM receptor and thereby mediates the adhesion of human neutrophils to different pathogens. In turn, these pathogens are phagocytosed and destroyed ; (Microbial infection) In the mosquito midgut, binds to the surface of parasite P.falciparum gametocytes and protects the parasite from alternative complement pathway-mediated elimination.
• Tissue Specificity: Expressed in the retinal pigment epithelium (at protein level) . CFH is one of the most abundant complement components in blood where the liver is the major source of CFH protein in vivo. in addition, CFH is secreted by additional cell types including monocytes, fibroblasts, or endothelial cells .
• 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

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atypical hemolytic uremic syndrome	DIS6FUDJ	Definitive	Semidominant	[1]
Primary membranoproliferative glomerulonephritis	DISW087P	Definitive	Autosomal recessive	[1]
Basal laminar drusen	DISXZO3H	Strong	Autosomal dominant	[2]
Complement factor H deficiency	DISAM9XP	Strong	Autosomal recessive	[3]
Hemolytic uremic syndrome, atypical, susceptibility to, 1	DIS5NG8S	Strong	Autosomal dominant	[4]
Dense deposit disease	DISLWJSE	Supportive	Autosomal recessive	[5]
Doyne honeycomb retinal dystrophy	DISKFNCT	Supportive	Autosomal dominant	[6]

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 H (CFH).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Complement factor H (CFH).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Complement factor H (CFH).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Complement factor H (CFH).	[10]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Complement factor H (CFH).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Complement factor H (CFH).	[12]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Complement factor H (CFH).	[13]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Complement factor H (CFH).	[14]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Complement factor H (CFH).	[15]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Complement factor H (CFH).	[16]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Complement factor H (CFH).	[17]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Complement factor H (CFH).	[18]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline decreases the expression of Complement factor H (CFH).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Complement factor H (CFH).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Complement factor H (CFH).	[22]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid decreases the expression of Complement factor H (CFH).	[23]

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 factor H (CFH).	[20]

References

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• [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.
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• [4] Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood. 2006 Aug 15;108(4):1267-79. doi: 10.1182/blood-2005-10-007252. Epub 2006 Apr 18.
• [5] Gene polymorphism of complement factor H in a Turkish patient with membranoproliferative glomerulonephritis type II. Iran J Kidney Dis. 2012 Mar;6(2):149-53.
• [6] Basal laminar drusen caused by compound heterozygous variants in the CFH gene. Am J Hum Genet. 2008 Feb;82(2):516-23. doi: 10.1016/j.ajhg.2007.11.007.
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• [9] Gene expression data from acetaminophen-induced toxicity in human hepatic in vitro systems and clinical liver samples. Data Brief. 2016 Mar 26;7:1052-1057. doi: 10.1016/j.dib.2016.03.069. eCollection 2016 Jun.
• [10] 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.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [13] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
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• [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] Cardiac toxicity from ethanol exposure in human-induced pluripotent stem cell-derived cardiomyocytes. Toxicol Sci. 2019 May 1;169(1):280-292.
• [17] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [18] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [19] 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.
• [20] 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.
• [21] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [22] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [23] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.