Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5BJSEX)

• DOT Name: Fibrinogen gamma chain (FGG)
• Gene Name: FGG
• Related Disease:
  Congenital fibrinogen deficiency
  Congenital afibrinogenemia
  Familial dysfibrinogenemia
  Thrombophilia
  Familial hypofibrinogenemia
• UniProt ID: FIBG_HUMAN
• PDB ID: 1DUG ; 1FIB ; 1FIC ; 1FID ; 1FZA ; 1FZB ; 1FZC ; 1FZE ; 1FZF ; 1FZG ; 1LT9 ; 1LTJ ; 1N86 ; 1N8E ; 1RE3 ; 1RE4 ; 1RF0 ; 1RF1 ; 2A45 ; 2FFD ; 2FIB ; 2H43 ; 2HLO ; 2HOD ; 2HPC ; 2HWL ; 2OYH ; 2OYI ; 2Q9I ; 2VDO ; 2VDP ; 2VDQ ; 2VDR ; 2VR3 ; 2XNX ; 2XNY ; 2Y7L ; 2Z4E ; 3BVH ; 3E1I ; 3FIB ; 3GHG ; 3H32 ; 3HUS ; 4B60
• Pfam ID: PF08702 ; PF00147
• Sequence:
  MSWSLHPRNLILYFYALLFLSSTCVAYVATRDNCCILDERFGSYCPTTCGIADFLSTYQT
  KVDKDLQSLEDILHQVENKTSEVKQLIKAIQLTYNPDESSKPNMIDAATLKSRKMLEEIM
  KYEASILTHDSSIRYLQEIYNSNNQKIVNLKEKVAQLEAQCQEPCKDTVQIHDITGKDCQ
  DIANKGAKQSGLYFIKPLKANQQFLVYCEIDGSGNGWTVFQKRLDGSVDFKKNWIQYKEG
  FGHLSPTGTTEFWLGNEKIHLISTQSAIPYALRVELEDWNGRTSTADYAMFKVGPEADKY
  RLTYAYFAGGDAGDAFDGFDFGDDPSDKFFTSHNGMQFSTWDNDNDKFEGNCAEQDGSGW
  WMNKCHAGHLNGVYYQGGTYSKASTPNGYDNGIIWATWKTRWYSMKKTTMKIIPFNRLTI
  GEGQQHHLGGAKQVRPEHPAETEYDSLYPEDDL
• Function: Together with fibrinogen alpha (FGA) and fibrinogen beta (FGB), polymerizes to form an insoluble fibrin matrix. Has a major function in hemostasis as one of the primary components of blood clots. In addition, functions during the early stages of wound repair to stabilize the lesion and guide cell migration during re-epithelialization. Was originally thought to be essential for platelet aggregation, based on in vitro studies using anticoagulated blood. However, subsequent studies have shown that it is not absolutely required for thrombus formation in vivo. Enhances expression of SELP in activated platelets via an ITGB3-dependent pathway. Maternal fibrinogen is essential for successful pregnancy. Fibrin deposition is also associated with infection, where it protects against IFNG-mediated hemorrhage. May also facilitate the antibacterial immune response via both innate and T-cell mediated pathways.
• Tissue Specificity: Detected in blood plasma (at protein level).
• KEGG Pathway:
  Complement and coagulation cascades (hsa04610)
  Platelet activation (hsa04611)
  Neutrophil extracellular trap formation (hsa04613)
  Staphylococcus aureus infection (hsa05150)
  Coro.virus disease - COVID-19 (hsa05171)
• Reactome Pathway:
  ER-Phagosome pathway (R-HSA-1236974)
  Common Pathway of Fibrin Clot Formation (R-HSA-140875)
  MyD88 (R-HSA-166058)
  Integrin cell surface interactions (R-HSA-216083)
  Integrin signaling (R-HSA-354192)
  GRB2 (R-HSA-354194)
  p130Cas linkage to MAPK signaling for integrins (R-HSA-372708)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  MyD88 deficiency (TLR2/4) (R-HSA-5602498)
  IRAK4 deficiency (TLR2/4) (R-HSA-5603041)
  MAP2K and MAPK activation (R-HSA-5674135)
  Regulation of TLR by endogenous ligand (R-HSA-5686938)
  Signaling by moderate kinase activity BRAF mutants (R-HSA-6802946)
  Signaling by high-kinase activity BRAF mutants (R-HSA-6802948)
  Signaling by BRAF and RAF1 fusions (R-HSA-6802952)
  Paradoxical activation of RAF signaling by kinase inactive BRAF (R-HSA-6802955)
  Post-translational protein phosphorylation (R-HSA-8957275)
  Signaling downstream of RAS mutants (R-HSA-9649948)
  Signaling by RAF1 mutants (R-HSA-9656223)
  Platelet degranulation (R-HSA-114608)
• BioCyc Pathway: MetaCyc:ENSG00000171557-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital fibrinogen deficiency	DIS84ZAR	Definitive	Semidominant	[1]
Congenital afibrinogenemia	DISGCW8D	Strong	Autosomal recessive	[2]
Familial dysfibrinogenemia	DISEOPCW	Strong	Autosomal dominant	[3]
Thrombophilia	DISQR7U7	Strong	Autosomal dominant	[4]
Familial hypofibrinogenemia	DIS7WFBL	Supportive	Autosomal dominant	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Fibrinogen gamma chain (FGG).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Fibrinogen gamma chain (FGG).	[20]

17 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 Fibrinogen gamma chain (FGG).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Fibrinogen gamma chain (FGG).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Fibrinogen gamma chain (FGG).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Fibrinogen gamma chain (FGG).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Fibrinogen gamma chain (FGG).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Fibrinogen gamma chain (FGG).	[12]
Menadione	DMSJDTY	Approved	Menadione increases the expression of Fibrinogen gamma chain (FGG).	[12]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Fibrinogen gamma chain (FGG).	[13]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone affects the expression of Fibrinogen gamma chain (FGG).	[14]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Fibrinogen gamma chain (FGG).	[15]
Gemcitabine	DMSE3I7	Approved	Gemcitabine affects the expression of Fibrinogen gamma chain (FGG).	[13]
Ursodeoxycholic acid	DMCUT21	Approved	Ursodeoxycholic acid affects the expression of Fibrinogen gamma chain (FGG).	[16]
LY2835219	DM93VBZ	Approved	LY2835219 decreases the expression of Fibrinogen gamma chain (FGG).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Fibrinogen gamma chain (FGG).	[18]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Fibrinogen gamma chain (FGG).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Fibrinogen gamma chain (FGG).	[21]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Fibrinogen gamma chain (FGG).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
adenosine diphosphate	DMFUHKP	Investigative	adenosine diphosphate increases the secretion of Fibrinogen gamma chain (FGG).	[23]

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] Congenital fibrinogen disorders: an update. Semin Thromb Hemost. 2013 Sep;39(6):585-95. doi: 10.1055/s-0033-1349222. Epub 2013 Jul 12.
• [3] A new heterozygous mutation in gamma fibrinogen gene leading to 326 Cys-->Ser substitution in fibrinogen Crdoba is associated with defective polymerization and familial hypodysfibrinogenemia. J Thromb Haemost. 2004 Feb;2(2):352-4. doi: 10.1111/j.1538-7836.2004.0584d.x.
• [4] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [5] Congenital hypofibrinogenemia: characterization of two missense mutations affecting fibrinogen assembly and secretion. Blood Cells Mol Dis. 2008 Nov-Dec;41(3):292-7. doi: 10.1016/j.bcmd.2008.06.004. Epub 2008 Aug 3.
• [6] 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.
• [7] 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.
• [8] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [12] Gene expression after treatment with hydrogen peroxide, menadione, or t-butyl hydroperoxide in breast cancer cells. Cancer Res. 2002 Nov 1;62(21):6246-54.
• [13] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [14] Proteomic analysis of human adipose tissue after rosiglitazone treatment shows coordinated changes to promote glucose uptake. Obesity (Silver Spring). 2010 Jan;18(1):27-34. doi: 10.1038/oby.2009.208. Epub 2009 Jun 25.
• [15] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [16] Gene expression profiling of early primary biliary cirrhosis: possible insights into the mechanism of action of ursodeoxycholic acid. Liver Int. 2008 Aug;28(7):997-1010. doi: 10.1111/j.1478-3231.2008.01744.x. Epub 2008 Apr 15.
• [17] Biological specificity of CDK4/6 inhibitors: dose response relationship, in vivo signaling, and composite response signature. Oncotarget. 2017 Jul 4;8(27):43678-43691. doi: 10.18632/oncotarget.18435.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Induction of fibrinogen and a subset of acute phase response genes involves a novel monokine which is mimicked by phorbol esters. J Biol Chem. 1987 Aug 5;262(22):10850-4.
• [20] 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.
• [21] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [22] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [23] Moderation of the platelet releasate response by aspirin. Blood. 2007 Jun 1;109(11):4786-92. doi: 10.1182/blood-2006-07-038539. Epub 2007 Feb 15.