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Plasminogen

FDA  APPROVED 2021, Ryplazim, 2021/6/4

Plasminogen;
Glu-plasminogen;
Plasminogen, human-tvmh;
Ryplazim (TN)

RYPLAZIM (plasminogen, human-tvmh)

Enzyme replacement (plasminogen), Plasminogen deficiency type 1

CAS: 9001-91-6

STN: 125659
Proper Name: plasminogen, human-tvmh
Tradename: RYPLAZIM
Manufacturer: Prometic Biotherapeutics Inc.
Indication: 

For the treatment of patients with plasminogen deficiency type 1 (hypoplasminogenemia)

READ  https://diapharma.com/plasminogen-plg/

On August 11, 2017 Prometic Biotherapeutics submitted a BLA (STN 125659) for a Drug Product (DP) RYPLAZIM, Plasminogen (Human). This drug product is indicated for replacement therapy in children and adults with plasminogen deficiency.

Plasmin is an important enzyme (EC 3.4.21.7) present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein is encoded by the PLG gene.[5]

Function

 Fibrinolysis (simplified). Blue arrows denote stimulation, and red arrows inhibition.

Plasmin is a serine protease that acts to dissolve fibrin blood clots. Apart from fibrinolysis, plasmin proteolyses proteins in various other systems: It activates collagenases, some mediators of the complement system, and weakens the wall of the Graafian follicle, leading to ovulation. Plasmin is also integrally involved in inflammation.[6] It cleaves fibrinfibronectinthrombospondin, laminin, and von Willebrand factor. Plasmin, like trypsin, belongs to the family of serine proteases.

Plasmin is released as a zymogen called plasminogen (PLG) from the liver into the systemic circulation. Two major glycoforms of plasminogen are present in humans – type I plasminogen contains two glycosylation moieties (N-linked to N289 and O-linked to T346), whereas type II plasminogen contains only a single O-linked sugar (O-linked to T346). Type II plasminogen is preferentially recruited to the cell surface over the type I glycoform. Conversely, type I plasminogen appears more readily recruited to blood clots.

In circulation, plasminogen adopts a closed, activation-resistant conformation. Upon binding to clots, or to the cell surface, plasminogen adopts an open form that can be converted into active plasmin by a variety of enzymes, including tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), kallikrein, and factor XII (Hageman factor). Fibrin is a cofactor for plasminogen activation by tissue plasminogen activator. Urokinase plasminogen activator receptor (uPAR) is a cofactor for plasminogen activation by urokinase plasminogen activator. The conversion of plasminogen to plasmin involves the cleavage of the peptide bond between Arg-561 and Val-562.[5][7][8][9]

Plasmin cleavage produces angiostatin.

Mechanism of plasminogen activation

Full length plasminogen comprises seven domains. In addition to a C-terminal chymotrypsin-like serine protease domain, plasminogen contains an N-terminal Pan Apple domain (PAp) together with five Kringle domains (KR1-5). The Pan-Apple domain contains important determinants for maintaining plasminogen in the closed form, and the kringle domains are responsible for binding to lysine residues present in receptors and substrates.

The X-ray crystal structure of closed plasminogen reveals that the PAp and SP domains maintain the closed conformation through interactions made throughout the kringle array .[9] Chloride ions further bridge the PAp / KR4 and SP / KR2 interfaces, explaining the physiological role of serum chloride in stabilizing the closed conformer. The structural studies also reveal that differences in glycosylation alter the position of KR3. These data help explain the functional differences between the type I and type II plasminogen glycoforms.[citation needed]

In closed plasminogen, access to the activation bond (R561/V562) targeted for cleavage by tPA and uPA is blocked through the position of the KR3/KR4 linker sequence and the O-linked sugar on T346. The position of KR3 may also hinder access to the activation loop. The Inter-domain interactions also block all kringle ligand-binding sites apart from that of KR-1, suggesting that the latter domain governs pro-enzyme recruitment to targets. Analysis of an intermediate plasminogen structure suggests that plasminogen conformational change to the open form is initiated through KR-5 transiently peeling away from the PAp domain. These movements expose the KR5 lysine-binding site to potential binding partners, and suggest a requirement for spatially distinct lysine residues in eliciting plasminogen recruitment and conformational change respectively.[9]

Mechanism of plasmin inactivation

Plasmin is inactivated by proteins such as α2-macroglobulin and α2-antiplasmin.[10] The mechanism of plasmin inactivation involves the cleavage of an α2-macroglobulin at the bait region (a segment of the aM that is particularly susceptible to proteolytic cleavage) by plasmin. This initiates a conformational change such that the α2-macroglobulin collapses about the plasmin. In the resulting α2-macroglobulin-plasmin complex, the active site of plasmin is sterically shielded, thus substantially decreasing the plasmin’s access to protein substrates. Two additional events occur as a consequence of bait region cleavage, namely (i) a h-cysteinyl-g-glutamyl thiol ester of the α2-macroglobulin becomes highly reactive and (ii) a major conformational change exposes a conserved COOH-terminal receptor binding domain. The exposure of this receptor binding domain allows the α2-macroglobulin protease complex to bind to clearance receptors and be removed from circulation.

Pathology

Plasmin deficiency may lead to thrombosis, as the clots are not adequately degraded. Plasminogen deficiency in mice leads to defective liver repair,[11] defective wound healing, reproductive abnormalities.[citation needed]

In humans, a rare disorder called plasminogen deficiency type I (Online Mendelian Inheritance in Man (OMIM): 217090) is caused by mutations of the PLG gene and is often manifested by ligneous conjunctivitis.

Interactions

Plasmin has been shown to interact with Thrombospondin 1,[12][13] Alpha 2-antiplasmin[14][15] and IGFBP3.[16] Moreover, plasmin induces the generation of bradykinin in mice and humans through high-molecular-weight kininogen cleavage.[17]

References

  1. Jump up to:a b c GRCh38: Ensembl release 89: ENSG00000122194 – Ensembl, May 2017
  2. Jump up to:a b c GRCm38: Ensembl release 89: ENSMUSG00000059481 – Ensembl, May 2017
  3. ^ “Human PubMed Reference:”National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ “Mouse PubMed Reference:”National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Jump up to:a b “Entrez Gene: plasminogen”.
  6. ^ Atsev S, Tomov N (December 2020). “Using antifibrinolytics to tackle neuroinflammation”Neural Regeneration Research15(12): 2203–2206. doi:10.4103/1673-5374.284979PMC 7749481PMID 32594031.
  7. ^ Miyata T, Iwanaga S, Sakata Y, Aoki N (October 1982). “Plasminogen Tochigi: inactive plasmin resulting from replacement of alanine-600 by threonine in the active site”Proc. Natl. Acad. Sci. U.S.A79 (20): 6132–6. Bibcode:1982PNAS…79.6132Mdoi:10.1073/pnas.79.20.6132PMC 347073PMID 6216475.
  8. ^ Forsgren M, Råden B, Israelsson M, Larsson K, Hedén LO (March 1987). “Molecular cloning and characterization of a full-length cDNA clone for human plasminogen”FEBS Lett213 (2): 254–60. doi:10.1016/0014-5793(87)81501-6PMID 3030813S2CID 9075872.
  9. Jump up to:a b c Law RH, Caradoc-Davies T, Cowieson N, Horvath AJ, Quek AJ, Encarnacao JA, Steer D, Cowan A, Zhang Q, Lu BG, Pike RN, Smith AI, Coughlin PB, Whisstock JC (2012). “The X-ray crystal structure of full-length human plasminogen”Cell Rep1 (3): 185–90. doi:10.1016/j.celrep.2012.02.012PMID 22832192.
  10. ^ Wu, Guojie; Quek, Adam J.; Caradoc-Davies, Tom T.; Ekkel, Sue M.; Mazzitelli, Blake; Whisstock, James C.; Law, Ruby H.P. (2019-03-05). “Structural studies of plasmin inhibition”. Biochemical Society Transactions47 (2): 541–557. doi:10.1042/bst20180211ISSN 0300-5127PMID 30837322.
  11. ^ Bezerra JA, Bugge TH, Melin-Aldana H, Sabla G, Kombrinck KW, Witte DP, Degen JL (December 21, 1999). “Plasminogen deficiency leads to impaired remodeling after a toxic injury to the liver”Proc. Natl. Acad. Sci. U.S.A. Proceedings of the National Academy of Sciences of the United States of America. 96 (26): 15143–8. Bibcode:1999PNAS…9615143Bdoi:10.1073/pnas.96.26.15143PMC 24787PMID 10611352.
  12. ^ Silverstein RL, Leung LL, Harpel PC, Nachman RL (November 1984). “Complex formation of platelet thrombospondin with plasminogen. Modulation of activation by tissue activator”J. Clin. Invest74 (5): 1625–33. doi:10.1172/JCI111578PMC 425339PMID 6438154.
  13. ^ DePoli P, Bacon-Baguley T, Kendra-Franczak S, Cederholm MT, Walz DA (March 1989). “Thrombospondin interaction with plasminogen. Evidence for binding to a specific region of the kringle structure of plasminogen”Blood73 (4): 976–82. doi:10.1182/blood.V73.4.976.976PMID 2522013.
  14. ^ Wiman B, Collen D (September 1979). “On the mechanism of the reaction between human alpha 2-antiplasmin and plasmin”J. Biol. Chem254 (18): 9291–7. doi:10.1016/S0021-9258(19)86843-6PMID 158022.
  15. ^ Shieh BH, Travis J (May 1987). “The reactive site of human alpha 2-antiplasmin”J. Biol. Chem262 (13): 6055–9. doi:10.1016/S0021-9258(18)45536-6PMID 2437112.
  16. ^ Campbell PG, Durham SK, Suwanichkul A, Hayes JD, Powell DR (August 1998). “Plasminogen binds the heparin-binding domain of insulin-like growth factor-binding protein-3”. Am. J. Physiol275 (2 Pt 1): E321-31. doi:10.1152/ajpendo.1998.275.2.E321PMID 9688635.
  17. ^ Marcos-Contreras OA, Martinez de Lizarrondo S, Bardou I, Orset C, Pruvost M, Anfray A, Frigout Y, Hommet Y, Lebouvier L, Montaner J, Vivien D, Gauberti M (August 2016). “Hyperfibrinolysis increases blood brain barrier permeability by a plasmin and bradykinin-dependent mechanism”Blood128 (20): 2423–2434. doi:10.1182/blood-2016-03-705384PMID 27531677.

Further reading

External links

PLG
Available structuresPDBOrtholog search: PDBe RCSBshowList of PDB id codes
Identifiers
AliasesPLG, plasminogen, plasmin, HAE4
External IDsOMIM173350 MGI97620 HomoloGene55452 GeneCardsPLG
showGene location (Human)
showGene location (Mouse)
showRNA expression pattern
showGene ontology
Orthologs
SpeciesHumanMouse
Entrez 5340 18815
Ensembl ENSG00000122194 ENSMUSG00000059481
UniProt P00747 P20918
RefSeq (mRNA) NM_001168338
NM_000301
 NM_008877
RefSeq (protein) NP_000292
NP_001161810
 NP_032903
Location (UCSC)Chr 6: 160.7 – 160.75 MbChr 17: 12.38 – 12.42 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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