Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4X9LDE)

• DOT Name: Kininogen-1 (KNG1)
• Synonyms: Alpha-2-thiol proteinase inhibitor; Fitzgerald factor; High molecular weight kininogen; HMWK; Williams-Fitzgerald-Flaujeac factor
• Gene Name: KNG1
• Related Disease:
  Congenital high-molecular-weight kininogen deficiency
  Angioedema, hereditary, 6
• UniProt ID: KNG1_HUMAN
• PDB ID: 1NY2; 2WOK; 4ASQ; 4ASR; 4ECB; 4ECC; 5I25; 6F27; 6F3V; 6F3W; 6F3X; 6F3Y; 7EIB; 7F2O; 7F6H; 7F6I; 7QOT; 7QOX
• Pfam ID: PF00031
• Sequence:
  MKLITILFLCSRLLLSLTQESQSEEIDCNDKDLFKAVDAALKKYNSQNQSNNQFVLYRIT
  EATKTVGSDTFYSFKYEIKEGDCPVQSGKTWQDCEYKDAAKAATGECTATVGKRSSTKFS
  VATQTCQITPAEGPVVTAQYDCLGCVHPISTQSPDLEPILRHGIQYFNNNTQHSSLFMLN
  EVKRAQRQVVAGLNFRITYSIVQTNCSKENFLFLTPDCKSLWNGDTGECTDNAYIDIQLR
  IASFSQNCDIYPGKDFVQPPTKICVGCPRDIPTNSPELEETLTHTITKLNAENNATFYFK
  IDNVKKARVQVVAGKKYFIDFVARETTCSKESNEELTESCETKKLGQSLDCNAEVYVVPW
  EKKIYPTVNCQPLGMISLMKRPPGFSPFRSSRIGEIKEETTVSPPHTSMAPAQDEERDSG
  KEQGHTRRHDWGHEKQRKHNLGHGHKHERDQGHGHQRGHGLGHGHEQQHGLGHGHKFKLD
  DDLEHQGGHVLDHGHKHKHGHGHGKHKNKGKKNGKHNGWKTEHLASSSEDSTTPSAQTQE
  KTEGPTPIPSLAKPGVTVTFSDFQDSDLIATMMPPISPAPIQSDDDWIPDIQIDPNGLSF
  NPISDFPDTTSPKCPGRPWKSVSEINPTTQMKESYYFDLTDGLS
• Function: Kininogens are inhibitors of thiol proteases. HMW-kininogen plays an important role in blood coagulation by helping to position optimally prekallikrein and factor XI next to factor XII; HMW-kininogen inhibits the thrombin- and plasmin-induced aggregation of thrombocytes. LMW-kininogen inhibits the aggregation of thrombocytes. LMW-kininogen is in contrast to HMW-kininogen not involved in blood clotting.; [Bradykinin]: The active peptide bradykinin is a potent vasodilatator that is released from HMW-kininogen shows a variety of physiological effects: (A) influence in smooth muscle contraction, (B) induction of hypotension, (C) natriuresis and diuresis, (D) decrease in blood glucose level, (E) it is a mediator of inflammation and causes (E1) increase in vascular permeability, (E2) stimulation of nociceptors (4E3) release of other mediators of inflammation (e.g. prostaglandins), (F) it has a cardioprotective effect (directly via bradykinin action, indirectly via endothelium-derived relaxing factor action).
• Tissue Specificity: Secreted in plasma. T-kinin is detected in malignant ovarian, colon and breast carcinomas, but not in benign tumors.
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  Sphingolipid sig.ling pathway (hsa04071)
  Neuroactive ligand-receptor interaction (hsa04080)
  Complement and coagulation cascades (hsa04610)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Regulation of actin cytoskeleton (hsa04810)
  Chagas disease (hsa05142)
  African trypanosomiasis (hsa05143)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  Intrinsic Pathway of Fibrin Clot Formation (R-HSA-140837)
  Peptide ligand-binding receptors (R-HSA-375276)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  G alpha (q) signalling events (R-HSA-416476)
  G alpha (i) signalling events (R-HSA-418594)
  Post-translational protein phosphorylation (R-HSA-8957275)
  Platelet degranulation (R-HSA-114608)

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 high-molecular-weight kininogen deficiency	DISWXLMY	Definitive	Autosomal recessive	[1]
Angioedema, hereditary, 6	DISVTD00	Limited	Unknown	[2]

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Nitric Oxide	DM1RBYG	Approved	Kininogen-1 (KNG1) increases the abundance of Nitric Oxide.	[14]
Chloride	DM1TJXA	Phase 3	Kininogen-1 (KNG1) increases the transport of Chloride.	[16]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Captopril	DM458UM	Approved	Kininogen-1 (KNG1) increases the Blood pressure decreased ADR of Captopril.	[15]

13 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 Kininogen-1 (KNG1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Kininogen-1 (KNG1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Kininogen-1 (KNG1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Kininogen-1 (KNG1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Kininogen-1 (KNG1).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Kininogen-1 (KNG1).	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Kininogen-1 (KNG1).	[8]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Kininogen-1 (KNG1).	[9]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the activity of Kininogen-1 (KNG1).	[10]
Lidocaine	DML4ZOT	Approved	Lidocaine decreases the activity of Kininogen-1 (KNG1).	[10]
Perindopril	DMOPZDT	Approved	Perindopril decreases the expression of Kininogen-1 (KNG1).	[12]
Mepyramine	DMB4SFH	Approved	Mepyramine decreases the activity of Kininogen-1 (KNG1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Kininogen-1 (KNG1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Olanzapine	DMPFN6Y	Approved	Olanzapine affects the phosphorylation of Kininogen-1 (KNG1).	[11]

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] Hereditary angioedema cosegregating with a novel kininogen 1 gene mutation changing the N-terminal cleavage site of bradykinin. Allergy. 2019 Dec;74(12):2479-2481. doi: 10.1111/all.13869. Epub 2019 Jun 7.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [9] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [10] Effects of capsaicin, bradykinin and prostaglandin E2 in the human skin. Br J Dermatol. 1992 Feb;126(2):111-7. doi: 10.1111/j.1365-2133.1992.tb07806.x.
• [11] 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.
• [12] Long-term treatment with perindopril ameliorates dobutamine-induced myocardial ischemia in patients with coronary artery disease. Jpn J Pharmacol. 2002 Jan;88(1):100-7. doi: 10.1254/jjp.88.100.
• [13] Inter- and intra-laboratory study to determine the reproducibility of toxicogenomics datasets. Toxicology. 2011 Nov 28;290(1):50-8.
• [14] Modifications induced by LDL from type 1 diabetic patients on endothelial cells obtained from human umbilical vein. Diabetes. 1999 Nov;48(11):2221-8. doi: 10.2337/diabetes.48.11.2221.
• [15] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [16] Interaction between bradykinin and natriuretic peptides via RGS protein activation in HEK-293 cells. Am J Physiol Cell Physiol. 2012 Dec 15;303(12):C1260-8. doi: 10.1152/ajpcell.00033.2012. Epub 2012 Oct 10.