Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI3TXBE)

• DOT Name: Vitamin K-dependent protein Z (PROZ)
• Gene Name: PROZ
• Related Disease:
  Nephropathy
  Acute coronary syndrome
  Behcet disease
  Cerebral infarction
  Pre-eclampsia
  Pyelonephritis
  Protein Z deficiency
  Sickle-cell anaemia
  Stroke
• UniProt ID: PROZ_HUMAN
• PDB ID: 3F1S; 3H5C
• Pfam ID: PF00008 ; PF14670 ; PF00594 ; PF00089
• Sequence:
  MAGCVPLLQGLVLVLALHRVEPSVFLPASKANDVLVRWKRAGSYLLEELFEGNLEKECYE
  EICVYEEAREVFENEVVTDEFWRRYKGGSPCISQPCLHNGSCQDSIWGYTCTCSPGYEGS
  NCELAKNECHPERTDGCQHFCLPGQESYTCSCAQGYRLGEDHKQCVPHDQCACGVLTSEK
  RAPDLQDLPWQVKLTNSEGKDFCGGVIIRENFVLTTAKCSLLHRNITVKTYFNRTSQDPL
  MIKITHVHVHMRYDADAGENDLSLLELEWPIQCPGAGLPVCTPEKDFAEHLLIPRTRGLL
  SGWARNGTDLGNSLTTRPVTLVEGEECGQVLNVTVTTRTYCERSSVAAMHWMDGSVVTRE
  HRGSWFLTGVLGSQPVGGQAHMVLVTKVSRYSLWFKQIMN
• Function: Appears to assist hemostasis by binding thrombin and promoting its association with phospholipid vesicles. Inhibits activity of the coagulation protease factor Xa in the presence of SERPINA10, calcium and phospholipids.
• Tissue Specificity: Plasma.
• Reactome Pathway:
  Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus (R-HSA-159763)
  Removal of aminoterminal propeptides from gamma-carboxylated proteins (R-HSA-159782)
  Gamma-carboxylation of protein precursors (R-HSA-159740)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nephropathy	DISXWP4P	Definitive	Altered Expression	[1]
Acute coronary syndrome	DIS7DYEW	Strong	Biomarker	[2]
Behcet disease	DISSYMBS	Strong	Altered Expression	[3]
Cerebral infarction	DISR1WNP	Strong	Genetic Variation	[4]
Pre-eclampsia	DISY7Q29	Strong	Biomarker	[5]
Pyelonephritis	DISAOX93	Strong	Biomarker	[6]
Protein Z deficiency	DISF296Z	Limited	Unknown	[7]
Sickle-cell anaemia	DIS5YNZB	Limited	Genetic Variation	[8]
Stroke	DISX6UHX	Limited	Genetic Variation	[9]

8 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 Vitamin K-dependent protein Z (PROZ).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Vitamin K-dependent protein Z (PROZ).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Vitamin K-dependent protein Z (PROZ).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Vitamin K-dependent protein Z (PROZ).	[13]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Vitamin K-dependent protein Z (PROZ).	[15]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Vitamin K-dependent protein Z (PROZ).	[16]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Vitamin K-dependent protein Z (PROZ).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Vitamin K-dependent protein Z (PROZ).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Vitamin K-dependent protein Z (PROZ).	[14]

References

• [1] Protein Z is reduced in chronic kidney disease and not elevated in patients on haemodialysis.Blood Coagul Fibrinolysis. 2008 Jan;19(1):23-5. doi: 10.1097/MBC.0b013e3282f09df2.
• [2] [Protein Z: a new regulator of coagulation in arterial vessels?].Ann Pharm Fr. 2004 Sep;62(5):316-22. doi: 10.1016/s0003-4509(04)94320-9.
• [3] Decreased protein Z concentrations complicating the hypercoagulable state of Behet's disease.Clin Appl Thromb Hemost. 2003 Jul;9(3):259-63. doi: 10.1177/107602960300900312.
• [4] Variation in coagulation and fibrinolysis genes evaluated for their contribution to cerebrovascular complications in adults with bacterial meningitis in the Netherlands.J Infect. 2018 Jul;77(1):54-59. doi: 10.1016/j.jinf.2018.03.007. Epub 2018 May 7.
• [5] Preeclampsia is associated with low concentrations of protein Z.J Matern Fetal Neonatal Med. 2007 Sep;20(9):661-7. doi: 10.1080/14767050701495011.
• [6] Pyelonephritis during pregnancy: a cause for an acquired deficiency of protein Z.J Matern Fetal Neonatal Med. 2008 Sep;21(9):629-37. doi: 10.1080/14767050802214659.
• [7] A naturally occurring E30Q mutation in the Gla domain of protein Z causes its impaired secretion and subsequent deficiency. Blood. 2005 Apr 15;105(8):3149-54. doi: 10.1182/blood-2004-06-2250. Epub 2004 Dec 30.
• [8] Protein Z and Endothelin-1 genetic polymorphisms in pediatric Egyptian sickle cell disease patients.J Clin Lab Anal. 2018 Feb;32(2):e22264. doi: 10.1002/jcla.22264. Epub 2017 May 26.
• [9] Circulating protein Z concentration, PROZ variants, and unexplained cerebral infarction in young and middle-aged adults.Thromb Haemost. 2017 Jan 5;117(1):149-157. doi: 10.1160/TH16-04-0277. Epub 2016 Sep 29.
• [10] 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.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [15] 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.
• [16] 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.
• [17] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.