Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT93MUNH)

• DOT Name: Coagulation factor XI (F11)
• Synonyms: FXI; EC 3.4.21.27; Plasma thromboplastin antecedent; PTA
• Gene Name: F11
• Related Disease: Congenital factor XI deficiency
• UniProt ID: FA11_HUMAN
• PDB ID: 1XX9 ; 1XXD ; 1XXF ; 1ZHM ; 1ZHP ; 1ZHR ; 1ZJD ; 1ZLR ; 1ZMJ ; 1ZML ; 1ZMN ; 1ZOM ; 1ZPB ; 1ZPC ; 1ZPZ ; 1ZRK ; 1ZSJ ; 1ZSK ; 1ZSL ; 1ZTJ ; 1ZTK ; 1ZTL ; 2FDA ; 2J8J ; 2J8L ; 3BG8 ; 3SOR ; 3SOS ; 4CR5 ; 4CR9 ; 4CRA ; 4CRB ; 4CRC ; 4CRD ; 4CRE ; 4CRF ; 4CRG ; 4D76 ; 4D7F ; 4D7G ; 4NA7 ; 4NA8 ; 4TY6 ; 4TY7 ; 4WXI ; 4X6M ; 4X6N ; 4X6O ; 4X6P ; 4Y8X ; 4Y8Y ; 4Y8Z ; 5E2O ; 5E2P ; 5EOD ; 5EOK ; 5EXL ; 5EXM ; 5EXN ; 5I25 ; 5Q0D ; 5Q0E ; 5Q0F ; 5Q0G ; 5Q0H ; 5QCK ; 5QCL ; 5QCM ; 5QCN ; 5QQO ; 5QQP ; 5QTT ; 5QTV ; 5QTW ; 5QTY ; 5TKS ; 5TKT ; 5TKU ; 5WB6 ; 6AOD ; 6C0S ; 6HHC ; 6I58 ; 6R8X ; 6TS4 ; 6TS5 ; 6TS6 ; 6TS7 ; 6TWB ; 6USY ; 6VLU ; 6VLV ; 6W50 ; 7CJ1 ; 7MBO ; 7QOT ; 7V0Z ; 7V10 ; 7V11 ; 7V12 ; 7V13 ; 7V14 ; 7V15 ; 7V16 ; 7V17 ; 7V18 ; 8BO3 ; 8BO4 ; 8BO5 ; 8BO6 ; 8BO7
• EC Number: 3.4.21.27
• Pfam ID: PF00024 ; PF00089
• Sequence:
  MIFLYQVVHFILFTSVSGECVTQLLKDTCFEGGDITTVFTPSAKYCQVVCTYHPRCLLFT
  FTAESPSEDPTRWFTCVLKDSVTETLPRVNRTAAISGYSFKQCSHQISACNKDIYVDLDM
  KGINYNSSVAKSAQECQERCTDDVHCHFFTYATRQFPSLEHRNICLLKHTQTGTPTRITK
  LDKVVSGFSLKSCALSNLACIRDIFPNTVFADSNIDSVMAPDAFVCGRICTHHPGCLFFT
  FFSQEWPKESQRNLCLLKTSESGLPSTRIKKSKALSGFSLQSCRHSIPVFCHSSFYHDTD
  FLGEELDIVAAKSHEACQKLCTNAVRCQFFTYTPAQASCNEGKGKCYLKLSSNGSPTKIL
  HGRGGISGYTLRLCKMDNECTTKIKPRIVGGTASVRGEWPWQVTLHTTSPTQRHLCGGSI
  IGNQWILTAAHCFYGVESPKILRVYSGILNQSEIKEDTSFFGVQEIIIHDQYKMAESGYD
  IALLKLETTVNYTDSQRPICLPSKGDRNVIYTDCWVTGWGYRKLRDKIQNTLQKAKIPLV
  TNEECQKRYRGHKITHKMICAGYREGGKDACKGDSGGPLSCKHNEVWHLVGITSWGEGCA
  QRERPGVYTNVVEYVDWILEKTQAV
• Function: Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX.
• Tissue Specificity: Isoform 2 is produced by platelets and megakaryocytes but absent from other blood cells.
• KEGG Pathway: Complement and coagulation cascades (hsa04610)
• Reactome Pathway:
  Defective F9 activation (R-HSA-9673221)
  Intrinsic Pathway of Fibrin Clot Formation (R-HSA-140837)
• BioCyc Pathway: MetaCyc:HS01617-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital factor XI deficiency	DISCF3MJ	Definitive	Semidominant	[1]

7 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 Coagulation factor XI (F11).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Coagulation factor XI (F11).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Coagulation factor XI (F11).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Coagulation factor XI (F11).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Coagulation factor XI (F11).	[3]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Coagulation factor XI (F11).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Coagulation factor XI (F11).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Coagulation factor XI (F11).	[8]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Iodoacetamide	DMM4XVL	Investigative	Iodoacetamide increases the cleavage of Coagulation factor XI (F11).	[9]

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] 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.
• [3] 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.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] 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.
• [8] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [9] Isolation and functional characterization of the active light chain of activated human blood coagulation factor XI. J Biol Chem. 1983 Aug 25;258(16):9669-75.