Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBFD2FU)

• DOT Name: Coagulation factor XII (F12)
• Synonyms: EC 3.4.21.38; Hageman factor; HAF
• Gene Name: F12
• Related Disease:
  Congenital factor XII deficiency
  Hereditary angioedema type 3
• UniProt ID: FA12_HUMAN
• PDB ID: 4BDW; 4BDX; 4XDE; 4XE4; 6B74; 6B77; 6GT6; 6L63; 6QF7; 6SZW; 6X0S; 6X0T; 7FBP; 7PRJ; 7PRK
• EC Number: 3.4.21.38
• Pfam ID: PF00008 ; PF00039 ; PF00040 ; PF00051 ; PF00089
• Sequence:
  MRALLLLGFLLVSLESTLSIPPWEAPKEHKYKAEEHTVVLTVTGEPCHFPFQYHRQLYHK
  CTHKGRPGPQPWCATTPNFDQDQRWGYCLEPKKVKDHCSKHSPCQKGGTCVNMPSGPHCL
  CPQHLTGNHCQKEKCFEPQLLRFFHKNEIWYRTEQAAVARCQCKGPDAHCQRLASQACRT
  NPCLHGGRCLEVEGHRLCHCPVGYTGAFCDVDTKASCYDGRGLSYRGLARTTLSGAPCQP
  WASEATYRNVTAEQARNWGLGGHAFCRNPDNDIRPWCFVLNRDRLSWEYCDLAQCQTPTQ
  AAPPTPVSPRLHVPLMPAQPAPPKPQPTTRTPPQSQTPGALPAKREQPPSLTRNGPLSCG
  QRLRKSLSSMTRVVGGLVALRGAHPYIAALYWGHSFCAGSLIAPCWVLTAAHCLQDRPAP
  EDLTVVLGQERRNHSCEPCQTLAVRSYRLHEAFSPVSYQHDLALLRLQEDADGSCALLSP
  YVQPVCLPSGAARPSETTLCQVAGWGHQFEGAEEYASFLQEAQVPFLSLERCSAPDVHGS
  SILPGMLCAGFLEGGTDACQGDSGGPLVCEDQAAERRLTLQGIISWGSGCGDRNKPGVYT
  DVAYYLAWIREHTVS
• Function: Factor XII is a serum glycoprotein that participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII first to alpha-factor XIIa and then trypsin cleaves it to beta-factor XIIa. Alpha-factor XIIa activates factor XI to factor XIa.
• KEGG Pathway: Complement and coagulation cascades (hsa04610)
• Reactome Pathway:
  Defective factor XII causes hereditary angioedema (R-HSA-9657688)
  Defective SERPING1 causes hereditary angioedema (R-HSA-9657689)
  Intrinsic Pathway of Fibrin Clot Formation (R-HSA-140837)
• BioCyc Pathway: MetaCyc:HS05500-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital factor XII deficiency	DISN4DF6	Definitive	Autosomal recessive	[1]
Hereditary angioedema type 3	DISFDZJ3	Definitive	Autosomal dominant	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Coagulation factor XII (F12) decreases the response to substance of Arsenic trioxide.	[18]
Methotrexate	DM2TEOL	Approved	Coagulation factor XII (F12) affects the response to substance of Methotrexate.	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Coagulation factor XII (F12).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Coagulation factor XII (F12).	[14]

14 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 Coagulation factor XII (F12).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Coagulation factor XII (F12).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Coagulation factor XII (F12).	[6]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Coagulation factor XII (F12).	[6]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Coagulation factor XII (F12).	[7]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Coagulation factor XII (F12).	[8]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Coagulation factor XII (F12).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Coagulation factor XII (F12).	[10]
Isoflavone	DM7U58J	Phase 4	Isoflavone affects the expression of Coagulation factor XII (F12).	[11]
Chondroitin sulfate	DM0N19Y	Phase 4	Chondroitin sulfate increases the activity of Coagulation factor XII (F12).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Coagulation factor XII (F12).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Coagulation factor XII (F12).	[15]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Coagulation factor XII (F12).	[16]
ELLAGIC ACID	DMX8BS5	Investigative	ELLAGIC ACID increases the activity of Coagulation factor XII (F12).	[17]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun. 2006 May 19;343(4):1286-9. doi: 10.1016/j.bbrc.2006.03.092.
• [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] 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.
• [6] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [7] Dissecting progressive stages of 5-fluorouracil resistance in vitro using RNA expression profiling. Int J Cancer. 2004 Nov 1;112(2):200-12. doi: 10.1002/ijc.20401.
• [8] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [9] 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.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Soy isoflavones alter expression of genes associated with cancer progression, including interleukin-8, in androgen-independent PC-3 human prostate cancer cells. J Nutr. 2006 Jan;136(1):75-82.
• [12] Contaminated heparin associated with adverse clinical events and activation of the contact system. N Engl J Med. 2008 Jun 5;358(23):2457-67. doi: 10.1056/NEJMoa0803200. Epub 2008 Apr 23.
• [13] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [14] 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.
• [15] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [16] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [17] Activation of Hageman factor (factor XII) by sulfatides and other agents in the absence of plasma proteases. J Lab Clin Med. 1983 Jul;102(1):31-45.
• [18] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.
• [19] 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.