Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ8OZ67)

• DOT Name: Protein Z-dependent protease inhibitor (SERPINA10)
• Synonyms: PZ-dependent protease inhibitor; PZI; Serpin A10
• Gene Name: SERPINA10
• Related Disease:
  Gastric cancer
  Haemophilia A
  Hemophilia
  Stomach cancer
  Thrombophilia
• UniProt ID: ZPI_HUMAN
• PDB ID: 3F1S; 3H5C; 4AFX; 4AJU
• Pfam ID: PF00079
• Sequence:
  MKVVPSLLLSVLLAQVWLVPGLAPSPQSPETPAPQNQTSRVVQAPKEEEEDEQEASEEKA
  SEEEKAWLMASRQQLAKETSNFGFSLLRKISMRHDGNMVFSPFGMSLAMTGLMLGATGPT
  ETQIKRGLHLQALKPTKPGLLPSLFKGLRETLSRNLELGLTQGSFAFIHKDFDVKETFFN
  LSKRYFDTECVPMNFRNASQAKRLMNHYINKETRGKIPKLFDEINPETKLILVDYILFKG
  KWLTPFDPVFTEVDTFHLDKYKTIKVPMMYGAGKFASTFDKNFRCHVLKLPYQGNATMLV
  VLMEKMGDHLALEDYLTTDLVETWLRNMKTRNMEVFFPKFKLDQKYEMHELLRQMGIRRI
  FSPFADLSELSATGRNLQVSRVLQRTVIEVDERGTEAVAGILSEITAYSMPPVIKVDRPF
  HFMIYEETSGMLLFLGRVVNPTLL
• Function: Inhibits activity of the coagulation protease factor Xa in the presence of PROZ, calcium and phospholipids. Also inhibits factor XIa in the absence of cofactors.
• Tissue Specificity: Expressed by the liver and secreted in plasma.
• Reactome Pathway:
  Post-translational protein phosphorylation (R-HSA-8957275)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gastric cancer	DISXGOUK	Strong	Biomarker	[1]
Haemophilia A	DIS0RQ2E	Strong	Biomarker	[2]
Hemophilia	DIS1S8P6	Strong	Biomarker	[2]
Stomach cancer	DISKIJSX	Strong	Biomarker	[1]
Thrombophilia	DISQR7U7	Strong	Biomarker	[3]

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 Protein Z-dependent protease inhibitor (SERPINA10).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein Z-dependent protease inhibitor (SERPINA10).	[12]

9 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 Protein Z-dependent protease inhibitor (SERPINA10).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein Z-dependent protease inhibitor (SERPINA10).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein Z-dependent protease inhibitor (SERPINA10).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein Z-dependent protease inhibitor (SERPINA10).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Protein Z-dependent protease inhibitor (SERPINA10).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Protein Z-dependent protease inhibitor (SERPINA10).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein Z-dependent protease inhibitor (SERPINA10).	[10]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Protein Z-dependent protease inhibitor (SERPINA10).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein Z-dependent protease inhibitor (SERPINA10).	[13]

References

• [1] Protein Z/protein Z-dependent protease inhibitor system in loco in human gastric cancer.Ann Hematol. 2014 May;93(5):779-84. doi: 10.1007/s00277-013-1941-8. Epub 2013 Oct 26.
• [2] Suppressing protein Z-dependent inhibition of factor Xa improves coagulation in hemophilia A.J Thromb Haemost. 2019 Jan;17(1):149-156. doi: 10.1111/jth.14337. Epub 2018 Dec 16.
• [3] Mutations within the protein Z-dependent protease inhibitor gene are associated with venous thromboembolic disease: a new form of thrombophilia.Br J Haematol. 2004 Oct;127(2):190-4. doi: 10.1111/j.1365-2141.2004.05189.x.
• [4] 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.
• [5] 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.
• [6] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [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] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.