Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT0CX3Q)

• DOT Name: Coagulation factor IX (F9)
• Synonyms: EC 3.4.21.22; Christmas factor; Plasma thromboplastin component; PTC
• Gene Name: F9
• Related Disease:
  Factor IX deficiency
  Mild hemophilia B
  Moderately severe hemophilia B
  Severe hemophilia B
  Symptomatic form of hemophilia B in female carriers
  Thrombophilia, X-linked, due to factor 9 defect
• UniProt ID: FA9_HUMAN
• PDB ID: 1CFH ; 1CFI ; 1EDM ; 1IXA ; 1MGX ; 1NL0 ; 1RFN ; 2WPH ; 2WPI ; 2WPJ ; 2WPK ; 2WPL ; 2WPM ; 3KCG ; 3LC3 ; 3LC5 ; 4WM0 ; 4WMA ; 4WMB ; 4WMI ; 4WMK ; 4WN2 ; 4WNH ; 4YZU ; 4Z0K ; 4ZAE ; 5EGM ; 5F84 ; 5F85 ; 5F86 ; 5JB8 ; 5JB9 ; 5JBA ; 5JBB ; 5JBC ; 5TNO ; 5TNT ; 5VYG ; 6MV4 ; 6RFK ; 6X5J ; 6X5L ; 6X5P ; 7AHV ; 8OL9
• EC Number: 3.4.21.22
• Pfam ID: PF00008 ; PF14670 ; PF00594 ; PF00089
• Sequence:
  MQRVNMIMAESPGLITICLLGYLLSAECTVFLDHENANKILNRPKRYNSGKLEEFVQGNL
  ERECMEEKCSFEEAREVFENTERTTEFWKQYVDGDQCESNPCLNGGSCKDDINSYECWCP
  FGFEGKNCELDVTCNIKNGRCEQFCKNSADNKVVCSCTEGYRLAENQKSCEPAVPFPCGR
  VSVSQTSKLTRAETVFPDVDYVNSTEAETILDNITQSTQSFNDFTRVVGGEDAKPGQFPW
  QVVLNGKVDAFCGGSIVNEKWIVTAAHCVETGVKITVVAGEHNIEETEHTEQKRNVIRII
  PHHNYNAAINKYNHDIALLELDEPLVLNSYVTPICIADKEYTNIFLKFGSGYVSGWGRVF
  HKGRSALVLQYLRVPLVDRATCLRSTKFTIYNNMFCAGFHEGGRDSCQGDSGGPHVTEVE
  GTSFLTGIISWGEECAMKGKYGIYTKVSRYVNWIKEKTKLT
• Function: Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca(2+) ions, phospholipids, and factor VIIIa.
• Tissue Specificity: Detected in blood plasma (at protein level) . Synthesized primarily in the liver and secreted in plasma.
• KEGG Pathway: Complement and coagulation cascades (hsa04610)
• Reactome Pathway:
  Intrinsic Pathway of Fibrin Clot Formation (R-HSA-140837)
  Gamma-carboxylation of protein precursors (R-HSA-159740)
  Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus (R-HSA-159763)
  Removal of aminoterminal propeptides from gamma-carboxylated proteins (R-HSA-159782)
  Protein hydroxylation (R-HSA-9629569)
  Defective factor IX causes thrombophilia (R-HSA-9672383)
  Defective cofactor function of FVIIIa variant (R-HSA-9672396)
  Defective F9 variant does not activate FX (R-HSA-9673202)
  Defective F9 secretion (R-HSA-9673218)
  Defective F9 activation (R-HSA-9673221)
  Defective gamma-carboxylation of F9 (R-HSA-9673240)
  Extrinsic Pathway of Fibrin Clot Formation (R-HSA-140834)
• BioCyc Pathway: MetaCyc:HS02329-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Factor IX deficiency	DISHN9SC	Definitive	X-linked	[1]
Mild hemophilia B	DIS2AY8W	Supportive	X-linked	[2]
Moderately severe hemophilia B	DISB9KYT	Supportive	X-linked	[2]
Severe hemophilia B	DISAYBYJ	Supportive	X-linked	[2]
Symptomatic form of hemophilia B in female carriers	DIS673P3	Supportive	X-linked	[2]
Thrombophilia, X-linked, due to factor 9 defect	DISLIC19	Limited	X-linked	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Warfarin	DMJYCVW	Approved	Coagulation factor IX (F9) increases the response to substance of Warfarin.	[10]
Coumarin	DM0N8ZM	Investigative	Coagulation factor IX (F9) increases the response to substance of Coumarin.	[11]

5 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 IX (F9).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Coagulation factor IX (F9).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Coagulation factor IX (F9).	[5]
Gentamicin	DMKINJO	Approved	Gentamicin increases the expression of Coagulation factor IX (F9).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Coagulation factor IX (F9).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Betaine	DMGRZW2	Approved	Betaine increases the secretion of Coagulation factor IX (F9).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Coagulation factor IX (F9).	[8]

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] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Aminoglycoside suppression of nonsense mutations in severe hemophilia. Blood. 2005 Nov 1;106(9):3043-8. doi: 10.1182/blood-2005-03-1307. Epub 2005 Jul 28.
• [7] Chemical chaperones improve protein secretion and rescue mutant factor VIII in mice with hemophilia A. PLoS One. 2012;7(9):e44505. doi: 10.1371/journal.pone.0044505. Epub 2012 Sep 4.
• [8] 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.
• [9] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [10] Variants in FIX propeptide associated with vitamin K antagonist hypersensitivity: functional analysis and additional data confirming the common founder mutations. Ann Hematol. 2018 Jun;97(6):1061-1069. doi: 10.1007/s00277-018-3264-2. Epub 2018 Feb 15.
• [11] Genetic predisposition to bleeding during oral anticoagulant therapy: evidence for common founder mutations (FIXVal-10 and FIXThr-10) and an independent CpG hotspot mutation (FIXThr-10). Thromb Haemost. 2001 Mar;85(3):454-7.