Details of Drug Off-Target (DOT)

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

• DOT Name: Plasma kallikrein (KLKB1)
• Synonyms: EC 3.4.21.34; Fletcher factor; Kininogenin; Plasma prekallikrein; PKK
• Gene Name: KLKB1
• Related Disease: Inherited prekallikrein deficiency
• UniProt ID: KLKB1_HUMAN
• PDB ID: 2ANW; 2ANY; 4OGX; 4OGY; 5F8T; 5F8X; 5F8Z; 5TJX; 6I44; 6O1G; 6O1S; 6T7P; 7N7X; 7QOX; 8A3Q; 8FGX
• EC Number: 3.4.21.34
• Pfam ID: PF00024 ; PF00089
• Sequence:
  MILFKQATYFISLFATVSCGCLTQLYENAFFRGGDVASMYTPNAQYCQMRCTFHPRCLLF
  SFLPASSINDMEKRFGCFLKDSVTGTLPKVHRTGAVSGHSLKQCGHQISACHRDIYKGVD
  MRGVNFNVSKVSSVEECQKRCTSNIRCQFFSYATQTFHKAEYRNNCLLKYSPGGTPTAIK
  VLSNVESGFSLKPCALSEIGCHMNIFQHLAFSDVDVARVLTPDAFVCRTICTYHPNCLFF
  TFYTNVWKIESQRNVCLLKTSESGTPSSSTPQENTISGYSLLTCKRTLPEPCHSKIYPGV
  DFGGEELNVTFVKGVNVCQETCTKMIRCQFFTYSLLPEDCKEEKCKCFLRLSMDGSPTRI
  AYGTQGSSGYSLRLCNTGDNSVCTTKTSTRIVGGTNSSWGEWPWQVSLQVKLTAQRHLCG
  GSLIGHQWVLTAAHCFDGLPLQDVWRIYSGILNLSDITKDTPFSQIKEIIIHQNYKVSEG
  NHDIALIKLQAPLNYTEFQKPICLPSKGDTSTIYTNCWVTGWGFSKEKGEIQNILQKVNI
  PLVTNEECQKRYQDYKITQRMVCAGYKEGGKDACKGDSGGPLVCKHNGMWRLVGITSWGE
  GCARREQPGVYTKVAEYMDWILEKTQSSDGKAQMQSPA
• Function: Participates in the surface-dependent activation of blood coagulation. Activates, in a reciprocal reaction, coagulation factor XII/F12 after binding to negatively charged surfaces. Releases bradykinin from HMW kininogen and may also play a role in the renin-angiotensin system by converting prorenin into renin.
• Tissue Specificity: Found in plasma (at protein level).
• KEGG Pathway: Complement and coagulation cascades (hsa04610)
• Reactome Pathway:
  Activation of Matrix Metalloproteinases (R-HSA-1592389)
  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)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Inherited prekallikrein deficiency	DISMLRSW	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Indomethacin	DMSC4A7	Approved	Plasma kallikrein (KLKB1) increases the Enterocolitis ADR of Indomethacin.	[15]

15 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 Plasma kallikrein (KLKB1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Plasma kallikrein (KLKB1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Plasma kallikrein (KLKB1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Plasma kallikrein (KLKB1).	[3]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Plasma kallikrein (KLKB1).	[5]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Plasma kallikrein (KLKB1).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Plasma kallikrein (KLKB1).	[7]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Plasma kallikrein (KLKB1).	[8]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Plasma kallikrein (KLKB1).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Plasma kallikrein (KLKB1).	[9]
Chondroitin sulfate	DM0N19Y	Phase 4	Chondroitin sulfate increases the activity of Plasma kallikrein (KLKB1).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Plasma kallikrein (KLKB1).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Plasma kallikrein (KLKB1).	[13]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Plasma kallikrein (KLKB1).	[14]
gingerol	DMNXYSM	Investigative	gingerol decreases the expression of Plasma kallikrein (KLKB1).	[6]

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 Plasma kallikrein (KLKB1).	[12]

References

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• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] A comprehensive analysis of Wnt/beta-catenin signaling pathway-related genes and crosstalk pathways in the treatment of As2O3 in renal cancer. Ren Fail. 2018 Nov;40(1):331-339.
• [6] In vitro and in vivo modulation of testosterone mediated alterations in apoptosis related proteins by [6]-gingerol. Mol Nutr Food Res. 2007 Dec;51(12):1492-502. doi: 10.1002/mnfr.200700197.
• [7] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [8] 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.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] 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.
• [13] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [14] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [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.