Hirudin is a naturally occurring

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

in the

salivary gland The salivary glands in many vertebrates including mammals are exocrine glands that produce saliva through a system of ducts. Humans have three paired major salivary glands ( parotid, submandibular, and sublingual), as well as hundreds of min ...

s of blood-sucking

leech Leeches are segmented parasitism, parasitic or Predation, predatory worms that comprise the Class (biology), subclass Hirudinea within the phylum Annelida. They are closely related to the Oligochaeta, oligochaetes, which include the earthwor ...

es (such as ''

Hirudo medicinalis ''Hirudo medicinalis'', or the European medicinal leech, is one of several species of leeches used as medicinal leeches. Other species of ''Hirudo'' sometimes also used as medicinal leeches include ''Hirudo orientalis, H. orientalis'', ''Hirudo ...

'') that has a blood

anticoagulant An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which ...

property. This is essential for the leeches' habit of feeding on blood, since it keeps a host's blood flowing after the worm's initial puncture of the skin. Hirudin (MEROPS I14.001) belongs to a superfamily (MEROPS IM) of

protease inhibitors Protease inhibitors (PIs) are medications that act by interfering with protease, enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS, hepatitis C and COVID-19. These protease inhibitors pre ...

that also includes haemadin (MEROPS I14.002) and antistasin (MEROPS I15).

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 In chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups. In in ...

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 Prothrombin (coagulation factor II) is encoded in the human by the F2-gene. It is proteolytically cleaved during the clotting process by the prothrombinase enzyme complex to form thrombin. Thrombin (Factor IIa) (, fibrose, thrombase, throm ...

, the

nitrogen Nitrogen is a chemical element; it has Symbol (chemistry), symbol N and atomic number 7. Nitrogen is a Nonmetal (chemistry), nonmetal and the lightest member of pnictogen, group 15 of the periodic table, often called the Pnictogen, pnictogens. ...

atom Atoms are the basic particles of the chemical elements. An atom consists of a atomic nucleus, nucleus of protons and generally neutrons, surrounded by an electromagnetically bound swarm of electrons. The chemical elements are distinguished fr ...

of residue 1 making a

hydrogen bond In chemistry, a hydrogen bond (H-bond) is a specific type of molecular interaction that exhibits partial covalent character and cannot be described as a purely electrostatic force. It occurs when a hydrogen (H) atom, Covalent bond, covalently b ...

with the Ser-195 O gamma atom of the

catalytic Catalysis () is the increase in reaction rate, rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst ...

site. The C-terminal domain makes numerous

electrostatic Electrostatics is a branch of physics that studies slow-moving or stationary electric charges. Since classical times, it has been known that some materials, such as amber, attract lightweight particles after rubbing. The Greek word (), mean ...

interactions with an

anion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conven ...

-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 A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

of the protein. However, recombinant techniques can be used to produce

homogeneous Homogeneity and heterogeneity are concepts relating to the uniformity of a substance, process or image. A homogeneous feature is uniform in composition or character (i.e., color, shape, size, weight, height, distribution, texture, language, i ...

preparations of hirudin.

Biological activity

A key event in the final stages of

blood coagulation Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of coagulatio ...

is the conversion of fibrinogen into

fibrin Fibrin (also called Factor Ia) is a fibrous protein, fibrous, non-globular protein involved in the Coagulation, clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerization, polymerize. ...

by the

serine protease Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. They are found ubiquitously in both eukaryotes and prokaryotes. Serin ...

enzyme

. 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 A thrombus ( thrombi) is a solid or semisolid aggregate from constituents of the blood (platelets, fibrin, red blood cells, white blood cells) within the circulatory system during life. A blood clot is the final product of the blood coagulatio ...

. The principal

inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...

in normal blood circulation is antithrombin. Similar to antithrombin, the anticoagulant activity of hirudin is based on its ability to inhibit the procoagulant activity of

. 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 Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...

hematoma A hematoma, also spelled haematoma, or blood suffusion is a localized bleeding outside of blood vessels, due to either disease or trauma including injury or surgery and may involve blood continuing to seep from broken capillaries. A hematoma is ...

s 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 Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Heparin is a blood anticoagulant that increases the activity of antithrombin. It is used in the treatment of myocardial infarction, ...

, as it does not interfere with the biological activity of other serum proteins, and can also act on complexed thrombin.

Medical use

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) using recombinant

biotechnology Biotechnology is a multidisciplinary field that involves the integration of natural sciences and Engineering Science, engineering sciences in order to achieve the application of organisms and parts thereof for products and services. Specialists ...

has been developed. This has led to the development and marketing of a number of hirudin-based anticoagulant pharmaceutical products, including: * recombinant hirudin derived from '' Hansenula'' (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 other direct thrombin inhibitors are derived chemically from hirudin.

References

External links

AgroMedic - Leech Farming, Medicinal Leeches, Malaysia Leeches (Hirudinaria Manillensis)
{{Antithrombotics Direct thrombin inhibitors Peptides

Structure

Biological activity

Medical use

See also

References

External links