hirudin

ヒルジン

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/04/17 05:30:22」(JST)

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Structure of Hirudin in complex with Thrombin.

Hirudin
crystallographic analysis at 3.0-angstroms resolution of the binding to human thrombin of four active site-directed inhibitors
Identifiers
Symbol	Hirudin
Pfam	PF00713
InterPro	IPR000429
SCOP	4htc
SUPERFAMILY	4htc
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Hirudin is a naturally occurring peptide in the salivary glands of medicinal leeches (such as Hirudo medicinalis) that has a blood anticoagulant property. This is fundamental for the leeches’ alimentary habit of hematophagy, since it keeps the blood flowing after the initial phlebotomy performed by the worm on the host’s skin.

Structure

During his years in Birmingham and Edinburgh, John Berry Haycraft had 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 three disulfide bonds and a C-terminal domain that is completely disordered when the protein is un-complexed in solution. Amino acid residues 1-3 form a parallel beta- strand with residues 214-217 of thrombin, the nitrogen atom of residue 1 making a hydrogen bond with the Ser-195 O gamma atom of the catalytic site. The C-terminal domain makes numerous electrostatic interactions with an anion-binding exosite of thrombin, while the last five residues are in a helical loop that forms many hydrophobic contacts. Natural hirudin contains a mixture of various isoforms of the protein. However, recombinant techniques can be used to produce homogeneous preparations of hirudin.

Biological activity

A key event in the final stages of blood coagulation is the conversion of fibrinogen into fibrin by the serine protease enzyme thrombin. Thrombin is produced from prothrombin, 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 a blood clot. The principal inhibitor of thrombin in normal blood circulation is antithrombin. Similar to antithrombin, the anticoagulatant activity of hirudin is based on its ability to inhibit the procoagulant activity of thrombin.

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. Therefore, hirudin prevents or dissolves the formation of clots and thrombi (i.e., it has a thrombolytic activity), and has therapeutic value in blood coagulation disorders, in the treatment of skin hematomas and of superficial varicose veins, either as an injectable or a topical application cream. In some aspects, hirudin has advantages over more commonly used anticoagulants and thrombolytics, such as heparin, as it does not interfere with the biological activity of other serum proteins, and can also act on complexed thrombin.

It is difficult to extract large amounts of hirudin from natural sources, so a method for producing and purifying this protein using recombinant biotechnology has been developed. This has led to the development and marketing of a number of hirudin-based anticoagulant pharmaceutical products, such as lepirudin (Refludan), hirudin derived from Hansenula (Thrombexx, Extrauma) and desirudin (Revasc/Iprivask). Several other direct thrombin inhibitors are derived chemically from hirudin.

See also

• Hirudotherapy
• Discovery and Development of Direct Thrombin Inhibitors

References

External links

• AgroMedic - Leech Farming,Medicinal Leeches,Malaysia Leeches(Hirudinaria Manillensis)

UpToDate Contents

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• 1. ヘパリン起因性血小板減少症のマネージメント management of heparin induced thrombocytopenia
• 2. 直接作用型経口抗凝固剤：用量および副作用 direct oral anticoagulants dosing and adverse effects
• 3. 血液透析中の抗凝固療法 hemodialysis anticoagulation
• 4. 非ST上昇型急性冠症候群における抗凝固療法 anticoagulant therapy in non st elevation acute coronary syndromes
• 5. ST上昇型心筋梗塞における抗凝固療法 anticoagulant therapy in acute st elevation myocardial infarction

English Journal

• A novel method for separation of caseins from milk by phosphates precipitation.

• Yen CH1, Lin YS, Tu CF.
• Preparative biochemistry & biotechnology.Prep Biochem Biotechnol.2015 Jan 2;45(1):18-32. doi: 10.1080/10826068.2013.877030.
• Milk protein of farm animals is difficult to isolate because of the presence of casein micelles, which are hard to separate from whey by using centrifugation or filtration. Insoluble casein micelles also create an obstacle for purification instruments to operate efficiently. The conventional method,
• PMID 24372141

• Poly(lactic-co-glycolic) acid microspheres encapsulated in Pluronic F-127 prolong hirudin delivery and improve functional recovery from a demyelination lesion.

• Sellers DL1, Kim TH2, Mount CW2, Pun SH2, Horner PJ3.
• Biomaterials.Biomaterials.2014 Oct;35(31):8895-902. doi: 10.1016/j.biomaterials.2014.06.051. Epub 2014 Jul 23.
• Components of the blood have been proposed as potential therapeutic targets for improving cellular regeneration after injury and neurodegenerative disease. In this work, thrombin is shown to increase endogenous neural progenitor proliferation in the intact murine spinal cord. A local injection of he
• PMID 25064804

• Genetic variants and evolutionary analyses of heparin cofactor II.

• Kumar A1, Bhandari A2, Sarde SJ3, Goswami C4.
• Immunobiology.Immunobiology.2014 Sep;219(9):713-28. doi: 10.1016/j.imbio.2014.05.003. Epub 2014 May 27.
• Heparin cofactor II (HCII) belongs to serpin superfamily and it acts as a thrombin inhibitor in the coagulation cascade, in a glycosaminoglycan-dependent pathway using the release of a sequestered hirudin-like N-terminal tail for interaction with thrombin. This serpin belongs to multiple member grou
• PMID 24950623

Japanese Journal

• 1P-072 3つのSS結合をもつヒルジンの酸化的リフォールディング経路の解析(蛋白質・物性(1),第46回日本生物物理学会年会)

• 生物物理 48(SUPPLEMENT_1), S32, 2008-10-25
• NAID 110007013234

• Thrombin-Stimulated Proliferation of Cultured Human Synovial Fibroblasts Through Proteolytic Activation of Proteinase-Activated Receptor-1

• Journal of pharmacological sciences 108(1), 104-111, 2008-09-20
• NAID 10024322567

• A development of LC-MS method combining ultrafiltration and lyophilization for determination of r-RGD-Hirudin in human serum

• Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 870(1), 27-31, 2008-07-01
• NAID 10028002411

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