Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGVH484)

• DOT Name: Vitamin K-dependent protein C (PROC)
• Synonyms: EC 3.4.21.69; Anticoagulant protein C; Autoprothrombin IIA; Blood coagulation factor XIV
• Gene Name: PROC
• Related Disease:
  Hereditary thrombophilia due to congenital protein C deficiency
  Thrombophilia due to protein C deficiency, autosomal dominant
  Thrombophilia due to protein C deficiency, autosomal recessive
• UniProt ID: PROC_HUMAN
• PDB ID: 1AUT; 1LQV; 3F6U; 3JTC; 4DT7; 6M3B; 6M3C; 8JRU; 8JRV
• EC Number: 3.4.21.69
• Pfam ID: PF14670 ; PF00594 ; PF00089
• Sequence:
  MWQLTSLLLFVATWGISGTPAPLDSVFSSSERAHQVLRIRKRANSFLEELRHSSLERECI
  EEICDFEEAKEIFQNVDDTLAFWSKHVDGDQCLVLPLEHPCASLCCGHGTCIDGIGSFSC
  DCRSGWEGRFCQREVSFLNCSLDNGGCTHYCLEEVGWRRCSCAPGYKLGDDLLQCHPAVK
  FPCGRPWKRMEKKRSHLKRDTEDQEDQVDPRLIDGKMTRRGDSPWQVVLLDSKKKLACGA
  VLIHPSWVLTAAHCMDESKKLLVRLGEYDLRRWEKWELDLDIKEVFVHPNYSKSTTDNDI
  ALLHLAQPATLSQTIVPICLPDSGLAERELNQAGQETLVTGWGYHSSREKEAKRNRTFVL
  NFIKIPVVPHNECSEVMSNMVSENMLCAGILGDRQDACEGDSGGPMVASFHGTWFLVGLV
  SWGEGCGLLHNYGVYTKVSRYLDWIHGHIRDKEAPQKSWAP
• Function: Protein C is a vitamin K-dependent serine protease that regulates blood coagulation by inactivating factors Va and VIIIa in the presence of calcium ions and phospholipids. Exerts a protective effect on the endothelial cell barrier function.
• Tissue Specificity: Plasma; synthesized in the liver.
• KEGG Pathway: Complement and coagulation cascades (hsa04610)
• Reactome Pathway:
  Common Pathway of Fibrin Clot Formation (R-HSA-140875)
  Gamma-carboxylation of protein precursors (R-HSA-159740)
  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)
  Cell surface interactions at the vascular wall (R-HSA-202733)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Post-translational protein phosphorylation (R-HSA-8957275)
  Intrinsic Pathway of Fibrin Clot Formation (R-HSA-140837)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary thrombophilia due to congenital protein C deficiency	DISRMIVY	Definitive	Semidominant	[1]
Thrombophilia due to protein C deficiency, autosomal dominant	DISYKRX3	Strong	Autosomal dominant	[2]
Thrombophilia due to protein C deficiency, autosomal recessive	DISYWFU6	Strong	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Warfarin	DMJYCVW	Approved	Vitamin K-dependent protein C (PROC) increases the response to substance of Warfarin.	[21]

19 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 C (PROC).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Vitamin K-dependent protein C (PROC).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Vitamin K-dependent protein C (PROC).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Vitamin K-dependent protein C (PROC).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Vitamin K-dependent protein C (PROC).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Vitamin K-dependent protein C (PROC).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Vitamin K-dependent protein C (PROC).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Vitamin K-dependent protein C (PROC).	[11]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the activity of Vitamin K-dependent protein C (PROC).	[12]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Vitamin K-dependent protein C (PROC).	[13]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate decreases the expression of Vitamin K-dependent protein C (PROC).	[14]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Vitamin K-dependent protein C (PROC).	[15]
Ardeparin	DMYRX8B	Approved	Ardeparin increases the activity of Vitamin K-dependent protein C (PROC).	[16]
Clomipramine	DMINRKW	Approved	Clomipramine increases the expression of Vitamin K-dependent protein C (PROC).	[17]
Vinorelbine	DMVXFYE	Approved	Vinorelbine decreases the expression of Vitamin K-dependent protein C (PROC).	[8]
Desogestrel	DM27U4Y	Approved	Desogestrel decreases the activity of Vitamin K-dependent protein C (PROC).	[18]
Gestodene	DM9R1YU	Phase 4	Gestodene decreases the activity of Vitamin K-dependent protein C (PROC).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Vitamin K-dependent protein C (PROC).	[19]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Vitamin K-dependent protein C (PROC).	[20]

1 Drug(s) Affected the Biochemical Pathways of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the metabolism of Vitamin K-dependent protein C (PROC).	[6]

References

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• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
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• [11] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [12] Thrombogenicity of intravenous 5-fluorouracil alone or in combination with cisplatin. Cancer. 1990 Feb 15;65(4):885-9. doi: 10.1002/1097-0142(19900215)65:4<885::aid-cncr2820650410>3.0.co;2-h.
• [13] 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.
• [14] Haemostatic effects of supraphysiological levels of testosterone in normal men. Thromb Haemost. 1995 Aug;74(2):693-7.
• [15] Clozapine-induced interstitial nephritis - a rare but important complication: a case report. J Med Case Rep. 2009 Aug 27;3:8574. doi: 10.4076/1752-1947-3-8574.
• [16] Rebound increase in thrombin generation and activity after cessation of intravenous heparin in patients with acute coronary syndromes. Circulation. 1995 Apr 1;91(7):1929-35. doi: 10.1161/01.cir.91.7.1929.
• [17] Reversible acute renal failure associated with clomipramine-induced interstitial nephritis. Clin Exp Nephrol. 2007 Sep;11(3):241-243. doi: 10.1007/s10157-007-0485-4. Epub 2007 Sep 28.
• [18] Oral contraceptives, thrombosis and haemostasis. Eur J Obstet Gynecol Reprod Biol. 2001 Apr;95(2):193-7. doi: 10.1016/s0301-2115(00)00489-9.
• [19] 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.
• [20] Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. Clin Exp Otorhinolaryngol. 2015 Dec;8(4):345-53. doi: 10.3342/ceo.2015.8.4.345. Epub 2015 Nov 10.
• [21] Building individualized medicine: prevention of adverse reactions to warfarin therapy. J Pharmacol Exp Ther. 2007 Aug;322(2):427-34. doi: 10.1124/jpet.106.117952. Epub 2007 May 11.