Details of Drug Off-Target (DOT)

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

• DOT Name: Plasminogen (PLG)
• Synonyms: EC 3.4.21.7
• Gene Name: PLG
• Related Disease:
  Hypoplasminogenemia
  Angioedema, hereditary, 4
• UniProt ID: PLMN_HUMAN
• PDB ID: 1B2I ; 1BML ; 1BUI ; 1CEA ; 1CEB ; 1DDJ ; 1HPJ ; 1HPK ; 1I5K ; 1KI0 ; 1KRN ; 1L4D ; 1L4Z ; 1PK4 ; 1PKR ; 1PMK ; 1QRZ ; 1RJX ; 2DOH ; 2DOI ; 2KNF ; 2L0S ; 2PK4 ; 3UIR ; 4A5T ; 4CIK ; 4DCB ; 4DUR ; 4DUU ; 5HPG ; 5UGD ; 5UGG ; 6D3X ; 6D3Y ; 6D3Z ; 6D40 ; 6OG4 ; 6OQJ ; 6OQK ; 6Q1U ; 6UZ4 ; 6UZ5 ; 7E50 ; 7THS ; 7UAH ; 8F7U ; 8F7V
• EC Number: 3.4.21.7
• Pfam ID: PF00051 ; PF00024 ; PF00089
• Sequence:
  MEHKEVVLLLLLFLKSGQGEPLDDYVNTQGASLFSVTKKQLGAGSIEECAAKCEEDEEFT
  CRAFQYHSKEQQCVIMAENRKSSIIIRMRDVVLFEKKVYLSECKTGNGKNYRGTMSKTKN
  GITCQKWSSTSPHRPRFSPATHPSEGLEENYCRNPDNDPQGPWCYTTDPEKRYDYCDILE
  CEEECMHCSGENYDGKISKTMSGLECQAWDSQSPHAHGYIPSKFPNKNLKKNYCRNPDRE
  LRPWCFTTDPNKRWELCDIPRCTTPPPSSGPTYQCLKGTGENYRGNVAVTVSGHTCQHWS
  AQTPHTHNRTPENFPCKNLDENYCRNPDGKRAPWCHTTNSQVRWEYCKIPSCDSSPVSTE
  QLAPTAPPELTPVVQDCYHGDGQSYRGTSSTTTTGKKCQSWSSMTPHRHQKTPENYPNAG
  LTMNYCRNPDADKGPWCFTTDPSVRWEYCNLKKCSGTEASVVAPPPVVLLPDVETPSEED
  CMFGNGKGYRGKRATTVTGTPCQDWAAQEPHRHSIFTPETNPRAGLEKNYCRNPDGDVGG
  PWCYTTNPRKLYDYCDVPQCAAPSFDCGKPQVEPKKCPGRVVGGCVAHPHSWPWQVSLRT
  RFGMHFCGGTLISPEWVLTAAHCLEKSPRPSSYKVILGAHQEVNLEPHVQEIEVSRLFLE
  PTRKDIALLKLSSPAVITDKVIPACLPSPNYVVADRTECFITGWGETQGTFGAGLLKEAQ
  LPVIENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDSGGPLVCFEKDKYILQGVTSW
  GLGCARPNKPGVYVRVSRFVTWIEGVMRNN
• Function: Plasmin dissolves the fibrin of blood clots and acts as a proteolytic factor in a variety of other processes including embryonic development, tissue remodeling, tumor invasion, and inflammation. In ovulation, weakens the walls of the Graafian follicle. It activates the urokinase-type plasminogen activator, collagenases and several complement zymogens, such as C1 and C5. Cleavage of fibronectin and laminin leads to cell detachment and apoptosis. Also cleaves fibrin, thrombospondin and von Willebrand factor. Its role in tissue remodeling and tumor invasion may be modulated by CSPG4. Binds to cells; Angiostatin is an angiogenesis inhibitor that blocks neovascularization and growth of experimental primary and metastatic tumors in vivo; (Microbial infection) ENO/enoloase from parasite P.falciparum (strain NF54) interacts with PLG present in the mosquito blood meal to promote the invasion of the mosquito midgut by the parasite ookinete. The catalytic active form, plasmin, is essential for the invasion of the mosquito midgut ; (Microbial infection) Binds to OspC on the surface of B.burgdorferi cells, possibly conferring an extracellular protease activity on the bacteria that allows it to traverse host tissue.
• Tissue Specificity: Present in plasma and many other extracellular fluids. It is synthesized in the liver.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Complement and coagulation cascades (hsa04610)
  Staphylococcus aureus infection (hsa05150)
  Influenza A (hsa05164)
• Reactome Pathway:
  Degradation of the extracellular matrix (R-HSA-1474228)
  Activation of Matrix Metalloproteinases (R-HSA-1592389)
  Signaling by PDGF (R-HSA-186797)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Dissolution of Fibrin Clot (R-HSA-75205)
  Platelet degranulation (R-HSA-114608)
• BioCyc Pathway: MetaCyc:HS04553-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypoplasminogenemia	DISS5W08	Definitive	Autosomal recessive	[1]
Angioedema, hereditary, 4	DISFERSP	Strong	Autosomal dominant	[2]

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 Plasminogen (PLG).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Plasminogen (PLG).	[14]

13 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 Plasminogen (PLG).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Plasminogen (PLG).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Plasminogen (PLG).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Plasminogen (PLG).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the activity of Plasminogen (PLG).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Plasminogen (PLG).	[8]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Plasminogen (PLG).	[10]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of Plasminogen (PLG).	[11]
Clofibrate	DMPC1J7	Approved	Clofibrate affects the expression of Plasminogen (PLG).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Plasminogen (PLG).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Plasminogen (PLG).	[8]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Plasminogen (PLG).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Plasminogen (PLG).	[15]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Cytarabine	DMZD5QR	Approved	Cytarabine affects the localization of Plasminogen (PLG).	[9]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Hereditary angioedema with a mutation in the plasminogen gene. Allergy. 2018 Feb;73(2):442-450. doi: 10.1111/all.13270. Epub 2017 Sep 7.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Arsenic trioxide downregulates the expression of annexin II in bone marrow cells from patients with acute myelogenous leukemia. Chin Med J (Engl). 2009 Sep 5;122(17):1969-73.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] Arsenic trioxide, retinoic acid and Ara-c regulated the expression of annexin II on the surface of APL cells, a novel co-receptor for plasminogen/tissue plasminogen activator. Thromb Res. 2002 Apr 1;106(1):63-70. doi: 10.1016/s0049-3848(02)00075-0.
• [10] 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.
• [11] Effects of oral and transvaginal ethinyl estradiol on hemostatic factors and hepatic proteins in a randomized, crossover study. J Clin Endocrinol Metab. 2007 Jun;92(6):2074-9. doi: 10.1210/jc.2007-0026. Epub 2007 Mar 20.
• [12] Effect of clofibrate on plasma proteins including components of the hemostatic mechanism. Clin Chim Acta. 1976 Jan 2;66(1):9-17. doi: 10.1016/0009-8981(76)90366-1.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] 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.
• [15] BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leukoc Biol. 2012 Dec;92(6):1147-54. doi: 10.1189/jlb.0312165. Epub 2012 Jul 16.