Hirudinis a naturally occurringpeptidein thesalivary glandsofblood-suckingleeches(such asHirudo medicinalis) that has a bloodanticoagulantproperty.[2]This is essential for the leeches' habit offeeding on blood,since it keeps a host's blood flowing after the worm's initialpuncture of the skin.
| Hirudin | |||||||||
|---|---|---|---|---|---|---|---|---|---|
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| Identifiers | |||||||||
| Symbol | Hirudin | ||||||||
| Pfam | PF00713 | ||||||||
| InterPro | IPR000429 | ||||||||
| SCOP2 | 4htc/SCOPe/SUPFAM | ||||||||
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Hirudin (MEROPS I14.001) belongs to a superfamily (MEROPS IM) ofprotease inhibitorsthat also includeshaemadin(MEROPS I14.002) andantistasin(MEROPS I15).[3][4]
Structure
editDuring his years in Birmingham and Edinburgh,John Berry Haycrafthad been actively engaged in research and published papers on the coagulation of blood, and in 1884, he discovered that the leech secreted a powerful anticoagulant, which he named hirudin, although it was not isolated until the 1950s, nor its structure fully determined until 1976. Full length hirudin is made up of 65 amino acids. These amino acids are organized into a compact N-terminal domain containing threedisulfide bondsand a C-terminal domain that is completely disordered when the protein isun-complexedin solution.[5][6]Amino acid residues1-3 form a parallel beta-strand with residues 214-217 ofthrombin,thenitrogenatomof residue 1 making ahydrogen bondwith theSer-195 O gamma atom of thecatalyticsite. The C-terminal domain makes numerouselectrostaticinteractions with ananion-bindingexositeof thrombin, while the last five residues are in ahelicalloopthat forms many hydrophobic contacts.[7]Natural hirudin contains a mixture of variousisoformsof the protein. However,recombinanttechniques can be used to producehomogeneouspreparations of hirudin.[8]
Biological activity
editA key event in the final stages ofblood coagulationis the conversion offibrinogenintofibrinby theserine proteaseenzymethrombin.[9]Thrombin is produced fromprothrombin,by the action of an enzyme, prothrombinase (Factor Xa along with Factor Va as a cofactor), in the final states of coagulation. Fibrin is then cross linked by factor XIII (Fibrin Stabilizing Factor) to form ablood clot.The principalinhibitorofthrombinin normal blood circulation isantithrombin.[8]Similar to antithrombin, the anticoagulant activity of hirudin is based on its ability to inhibit the procoagulant activity ofthrombin.
Hirudin is the most potent natural inhibitor of thrombin. Unlike antithrombin, hirudin binds to and inhibits only the activated thrombin, with a specific activity on fibrinogen.[8]Therefore, hirudin prevents or dissolves the formation of clots andthrombi(i.e., it has athrombolytic activity)[citation needed],and has therapeutic value inblood coagulation disorders,in the treatment ofskinhematomasand of superficialvaricose veins,either as an injectable or a topical application cream. In some aspects, hirudin has advantages over more commonly used anticoagulants and thrombolytics, such asheparin,as it does not interfere with the biological activity of otherserum proteins,and can also act oncomplexedthrombin.
Medical use
edit| Hirudin variant-1 | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Organism | |||||||
| Symbol | ? | ||||||
| UniProt | P01050 | ||||||
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It is difficult to extract large amounts of hirudin from natural sources, so a method for producing and purifying this protein (specifically P01050 in the infobox) usingrecombinantbiotechnologyhas been developed. This has led to the development and marketing of a number of hirudin-based anticoagulant pharmaceutical products, including:
- recombinant hirudin derived fromHansenula(Thrombexx, Extrauma)
- lepirudin(Refludan) – differs by one amino acid substitution and removal of sulfate group on Tyr63
- desirudin(Revasc/Iprivask) – differs by removal of sulfate group on Tyr63
- bivalirudin– peptide fragment
Several otherdirect thrombin inhibitorsare derived chemically from hirudin.
See also
editReferences
edit- ^PDB:4HTC
- ^"IV. On the action of a secretion obtained from the medicinal leech on the coagulation of the blood".Proceedings of the Royal Society of London.36(228–231): 478–487. 1883.doi:10.1098/rspl.1883.0135.
- ^"InterPro".www.ebi.ac.uk.
- ^"Clan IM".MEROPS - the Peptidase Database.
- ^Folkers PJ, Clore GM, Driscoll PC, Dodt J, Köhler S, Gronenborn AM (Mar 1989). "Solution structure of recombinant hirudin and the Lys-47----Glu mutant: a nuclear magnetic resonance and hybrid distance geometry-dynamical simulated annealing study".Biochemistry.28(6): 2601–2617.doi:10.1021/bi00432a038.PMID2567183.S2CID29110118.
- ^Haruyama H, Wüthrich K (May 1989). "Conformation of recombinant desulfatohirudin in aqueous solution determined by nuclear magnetic resonance".Biochemistry.28(10): 4301–4312.doi:10.1021/bi00436a027.PMID2765488.
- ^Rydel TJ, Ravichandran KG, Tulinsky A, Bode W, Huber R, Roitsch C, Fenton JW (Jul 1990). "The structure of a complex of recombinant hirudin and human alpha-thrombin".Science.249(4966): 277–80.Bibcode:1990Sci...249..277R.doi:10.1126/science.2374926.PMID2374926.
- ^abcRydel TJ, Tulinsky A, Bode W, Huber R (Sep 1991). "Refined structure of the hirudin-thrombin complex".Journal of Molecular Biology.221(2): 583–601.doi:10.1016/0022-2836(91)80074-5.PMID1920434.
- ^Fenton JW, Ofosu FA, Brezniak DV, Hassouna HI (1998). "Thrombin and antithrombotics".Seminars in Thrombosis and Hemostasis.24(2): 87–91.doi:10.1055/s-2007-995828.PMID9579630.