Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBK0GG7)

• DOT Name: Kallistatin (SERPINA4)
• Synonyms: Kallikrein inhibitor; Peptidase inhibitor 4; PI-4; Serpin A4
• Gene Name: SERPINA4
• Related Disease:
  Myocardial infarction
  Renal agenesis
  Renal hypodysplasia/aplasia 1
  Breast neoplasm
  Colonic neoplasm
  Enterocolitis
  Hepatocellular carcinoma
  Hypogonadism
  Hypogonadotropic hypogonadism
  Intellectual disability
  Intellectual disability, X-linked 1
  Klinefelter syndrome
  leukaemia
  Leukemia
  Lung cancer
  Lung carcinoma
  Malignant mesothelioma
  Mental disorder
  Neoplasm
  Non-alcoholic fatty liver disease
  Obesity
  Osteoarthritis
  Schizophrenia
  Vesicoureteral reflux
  X-linked lymphoproliferative syndrome
  Hypogonadotropic hypogonadism 7 with or without anosmia
  Kallmann syndrome
  Renal agenesis, unilateral
  X-linked adrenal hypoplasia congenita
  Hereditary angioedema
  Arthritis
  Colorectal carcinoma
  Orofaciodigital syndrome I
• UniProt ID: KAIN_HUMAN
• PDB ID: 6F02
• Pfam ID: PF00079
• Sequence:
  MHLIDYLLLLLVGLLALSHGQLHVEHDGESCSNSSHQQILETGEGSPSLKIAPANADFAF
  RFYYLIASETPGKNIFFSPLSISAAYAMLSLGACSHSRSQILEGLGFNLTELSESDVHRG
  FQHLLHTLNLPGHGLETRVGSALFLSHNLKFLAKFLNDTMAVYEAKLFHTNFYDTVGTIQ
  LINDHVKKETRGKIVDLVSELKKDVLMVLVNYIYFKALWEKPFISSRTTPKDFYVDENTT
  VRVPMMLQDQEHHWYLHDRYLPCSVLRMDYKGDATVFFILPNQGKMREIEEVLTPEMLMR
  WNNLLRKRNFYKKLELHLPKFSISGSYVLDQILPRLGFTDLFSKWADLSGITKQQKLEAS
  KSFHKATLDVDEAGTEAAAATSFAIKFFSAQTNRHILRFNRPFLVVIFSTSTQSVLFLGK
  VVDPTKP
• Function: Inhibits human amidolytic and kininogenase activities of tissue kallikrein. Inhibition is achieved by formation of an equimolar, heat- and SDS-stable complex between the inhibitor and the enzyme, and generation of a small C-terminal fragment of the inhibitor due to cleavage at the reactive site by tissue kallikrein.
• Tissue Specificity: Expressed by the liver and secreted in plasma.
• Reactome Pathway: Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Myocardial infarction	DIS655KI	Definitive	Biomarker	[1]
Renal agenesis	DIS0M9AF	Definitive	Genetic Variation	[2]
Renal hypodysplasia/aplasia 1	DISOH8XN	Definitive	Genetic Variation	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[4]
Enterocolitis	DISYACTL	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Therapeutic	[6]
Hypogonadism	DISICMNI	Strong	Genetic Variation	[7]
Hypogonadotropic hypogonadism	DIS8JSKR	Strong	Genetic Variation	[8]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[9]
Intellectual disability, X-linked 1	DISET38E	Strong	Genetic Variation	[9]
Klinefelter syndrome	DISOUI7W	Strong	Genetic Variation	[8]
leukaemia	DISS7D1V	Strong	Biomarker	[10]
Leukemia	DISNAKFL	Strong	Biomarker	[10]
Lung cancer	DISCM4YA	Strong	Biomarker	[11]
Lung carcinoma	DISTR26C	Strong	Biomarker	[11]
Malignant mesothelioma	DISTHJGH	Strong	Biomarker	[12]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[14]
Obesity	DIS47Y1K	Strong	Genetic Variation	[15]
Osteoarthritis	DIS05URM	Strong	Biomarker	[16]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[17]
Vesicoureteral reflux	DISUL6SA	Strong	Genetic Variation	[13]
X-linked lymphoproliferative syndrome	DISA7MJ4	Strong	Biomarker	[18]
Hypogonadotropic hypogonadism 7 with or without anosmia	DISPBWEU	moderate	Genetic Variation	[19]
Kallmann syndrome	DISO3HDG	moderate	Genetic Variation	[19]
Renal agenesis, unilateral	DIS53ZJ8	moderate	Genetic Variation	[20]
X-linked adrenal hypoplasia congenita	DISNMXY8	moderate	Genetic Variation	[21]
Hereditary angioedema	DIS8X53J	Disputed	Genetic Variation	[22]
Arthritis	DIST1YEL	Limited	Genetic Variation	[23]
Colorectal carcinoma	DIS5PYL0	Limited	Genetic Variation	[24]
Orofaciodigital syndrome I	DIST27XL	Limited	Genetic Variation	[25]

8 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 Kallistatin (SERPINA4).	[26]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Kallistatin (SERPINA4).	[27]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Kallistatin (SERPINA4).	[28]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Kallistatin (SERPINA4).	[29]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Kallistatin (SERPINA4).	[30]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Kallistatin (SERPINA4).	[30]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Kallistatin (SERPINA4).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Kallistatin (SERPINA4).	[33]

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 increases the methylation of Kallistatin (SERPINA4).	[32]

References

• [1] Novel role of kallistatin in protection against myocardial ischemia-reperfusion injury by preventing apoptosis and inflammation.Hum Gene Ther. 2006 Dec;17(12):1201-13. doi: 10.1089/hum.2006.17.1201.
• [2] Heterogeneity in the mutations responsible for X chromosome-linked Kallmann syndrome.Hum Mol Genet. 1993 Apr;2(4):373-7. doi: 10.1093/hmg/2.4.373.
• [3] Kallistatin is a new inhibitor of angiogenesis and tumor growth.Blood. 2002 Nov 1;100(9):3245-52. doi: 10.1182/blood-2002-01-0185.
• [4] Inhibition of angiogenesis and HCT-116 xenograft tumor growth in mice by kallistatin.World J Gastroenterol. 2007 Sep 14;13(34):4615-9. doi: 10.3748/wjg.v13.i34.4615.
• [5] The role of plasma high molecular weight kininogen in experimental intestinal and systemic inflammation.Arch Med Res. 2005 Jan-Feb;36(1):87-95. doi: 10.1016/j.arcmed.2005.02.001.
• [6] Combining kallistatin gene therapy and meloxicam to treat hepatocellular carcinoma in mice. Cancer Sci. 2009 Nov;100(11):2226-33. doi: 10.1111/j.1349-7006.2009.01306.x. Epub 2009 Aug 4.
• [7] Variable penetrance of hypogonadism in a sibship with Kallmann syndrome due to a deletion of the KAL gene.Am J Med Genet. 1995 Jul 3;57(3):476-8. doi: 10.1002/ajmg.1320570323.
• [8] Genetics of human hypogonadotropic hypogonadism.Am J Med Genet. 1999 Dec 29;89(4):240-8. doi: 10.1002/(sici)1096-8628(19991229)89:4<240::aid-ajmg8>3.0.co;2-7.
• [9] Analysis of an interstitial deletion in a patient with Kallmann syndrome, X-linked ichthyosis and mental retardation.Clin Genet. 1998 Jul;54(1):45-51. doi: 10.1111/j.1399-0004.1998.tb03692.x.
• [10] Blocking the proliferation of human tumor cell lines by peptidase inhibitors from Bauhinia seeds.Planta Med. 2013 Mar;79(3-4):227-35. doi: 10.1055/s-0032-1328156. Epub 2013 Jan 23.
• [11] Inhibition of experimental lung metastasis by systemic lentiviral delivery of kallistatin.BMC Cancer. 2010 May 31;10:245. doi: 10.1186/1471-2407-10-245.
• [12] Early detection of malignant pleural mesothelioma in asbestos-exposed individuals with a noninvasive proteomics-based surveillance tool.PLoS One. 2012;7(10):e46091. doi: 10.1371/journal.pone.0046091. Epub 2012 Oct 3.
• [13] Familial Kallmann syndrome: a novel splice acceptor mutation in the KAL gene.Hum Mutat. 1998;11(4):340-2.
• [14] Novel protective role of kallistatin in obesity by limiting adipose tissue low grade inflammation and oxidative stress.Metabolism. 2018 Oct;87:123-135. doi: 10.1016/j.metabol.2018.04.004. Epub 2018 Apr 18.
• [15] Idiopathic gonadotrophin deficiency: genetic questions addressed through phenotypic characterization.Clin Endocrinol (Oxf). 2001 Aug;55(2):163-74. doi: 10.1046/j.1365-2265.2001.01277.x.
• [16] Adenovirus-mediated kallistatin gene transfer ameliorates disease progression in a rat model of osteoarthritis induced by anterior cruciate ligament transection.Hum Gene Ther. 2009 Feb;20(2):147-58. doi: 10.1089/hum.2008.096.
• [17] Kallmann syndrome gene (KAL-X) is not mutated in schizophrenia.Am J Med Genet. 1999 Feb 5;88(1):34-7. doi: 10.1002/(sici)1096-8628(19990205)88:1<34::aid-ajmg6>3.0.co;2-6.
• [18] Activation-dependent T cell expression of the X-linked lymphoproliferative disease gene product SLAM-associated protein and its assessment for patient detection.Int Immunol. 2002 Oct;14(10):1215-23. doi: 10.1093/intimm/dxf084.
• [19] Mutation analysis of the KAL gene in female patients with gonadotropin-releasing hormone deficiency.Yonsei Med J. 2004 Feb 29;45(1):107-12. doi: 10.3349/ymj.2004.45.1.107.
• [20] Renal abnormalities in patients with Kallmann syndrome.BJU Int. 1999 Mar;83(4):383-6. doi: 10.1046/j.1464-410x.1999.00027.x.
• [21] Genetics of hypogonadotropic hypogonadism.J Endocrinol Invest. 2000 Oct;23(9):560-5. doi: 10.1007/BF03343776.
• [22] Novel MASP-2 inhibitors developed via directed evolution of human TFPI1 are potent lectin pathway inhibitors.J Biol Chem. 2019 May 17;294(20):8227-8237. doi: 10.1074/jbc.RA119.008315. Epub 2019 Apr 5.
• [23] Prophylactic adenovirus-mediated human kallistatin gene therapy suppresses rat arthritis by inhibiting angiogenesis and inflammation.Arthritis Rheum. 2005 Apr;52(4):1319-24. doi: 10.1002/art.20991.
• [24] Array CGH identifies distinct DNA copy number profiles of oncogenes and tumor suppressor genes in chromosomal- and microsatellite-unstable sporadic colorectal carcinomas.J Mol Med (Berl). 2007 Mar;85(3):293-304. doi: 10.1007/s00109-006-0126-5. Epub 2006 Dec 2.
• [25] The oral-facial-digital syndrome type 1 (OFD1), a cause of polycystic kidney disease and associated malformations, maps to Xp22.2-Xp22.3.Hum Mol Genet. 1997 Jul;6(7):1163-7. doi: 10.1093/hmg/6.7.1163.
• [26] 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.
• [27] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [28] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [29] 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.
• [30] 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.
• [31] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [32] 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.
• [33] 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.