Hirudin is a naturally occurring
peptidePeptides are short polymers formed from the linking, in a defined order, of α-amino acids. The link between one amino acid residue and the next is called an amide bond or a peptide bond....
in the
salivary glandThe salivary glands in mammals are exocrine glands, glands with ducts, that produce saliva. They also secrete amylase, an enzyme that breaks down starch into glucose...
s of medicinal
leechLeeches are annelids comprising the subclass Hirudinea. There are freshwater, terrestrial, and marine leeches. Like the Oligochaeta, they share the presence of a clitellum. Like earthworms, leeches are hermaphrodites...
es (such as
Hirudo medicinalis) that has a blood
anticoagulantAn anticoagulant is a substance that prevents coagulation; that is, it stops blood from clotting. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders...
property. This is fundamental for the leeches’ alimentary habit of
hematophagyHematophagy is the habit of certain animals of feeding on blood...
, since it keeps the blood flowing after the initial
phlebotomyPhlebotomy may refer to:* Venipuncture, the practice of collecting blood samples* The main practice of a phlebotomist, an individual trained to draw blood* Bloodletting, the ancient medical practice* Phlebotomy...
performed by the worm on the host’s skin.
In 1884, the British physiologist John Berry Haycraft discovered that the leech secreted a powerful anticoagulant, which he named hirudin, though it was not isolated until the 1950s, nor its structure fully determined until 1976.
Hirudin is a naturally occurring
peptidePeptides are short polymers formed from the linking, in a defined order, of α-amino acids. The link between one amino acid residue and the next is called an amide bond or a peptide bond....
in the
salivary glandThe salivary glands in mammals are exocrine glands, glands with ducts, that produce saliva. They also secrete amylase, an enzyme that breaks down starch into glucose...
s of medicinal
leechLeeches are annelids comprising the subclass Hirudinea. There are freshwater, terrestrial, and marine leeches. Like the Oligochaeta, they share the presence of a clitellum. Like earthworms, leeches are hermaphrodites...
es (such as
Hirudo medicinalis) that has a blood
anticoagulantAn anticoagulant is a substance that prevents coagulation; that is, it stops blood from clotting. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders...
property. This is fundamental for the leeches’ alimentary habit of
hematophagyHematophagy is the habit of certain animals of feeding on blood...
, since it keeps the blood flowing after the initial
phlebotomyPhlebotomy may refer to:* Venipuncture, the practice of collecting blood samples* The main practice of a phlebotomist, an individual trained to draw blood* Bloodletting, the ancient medical practice* Phlebotomy...
performed by the worm on the host’s skin.
Structure
In 1884, the British physiologist John Berry Haycraft discovered that the leech secreted a powerful anticoagulant, which he named hirudin, though 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 organised into a compact N-terminal domain containing three disulfide bonds and a C-terminal domain which is completely disordered, when the protein is
un-complexedA multiprotein complex is a group of two or more proteins. Protein complexes are a form of quaternary structure. Proteins in a protein complex are linked by non-covalent protein-protein interactions, and different protein complexes have different degrees of stability over time...
in solution. Natural hirudin contains a mixture of various
isoformsA protein isoform is any of several different forms of the same protein. Different forms of a protein may be produced from related genes, or may arise from the same gene by alternative splicing. A large number of isoforms are caused by single nucleotide polymorphisms or SNPs, small genetic...
of the protein. However,
recombinantRecombinant may refer to :* A recombinant organism - an organism that contains a different combination of alleles from either of its parents. See Recombination.* Recombinant DNA - a form of artificial DNA...
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
fibrinFibrin is a fibrous protein involved in the clotting of blood, and is non globular. It is a fibrillar protein that is polymerised to form a "mesh" that forms a hemostatic plug or clot over a wound site.Fibrin is made from fibrinogen, a soluble plasma glycoprotein that is synthesised by the liver...
by the
serine proteaseSerine proteases or serine endopeptidases are proteases in which one of the amino acids at the active site is serine....
enzyme
thrombinThrombin also commonly called pro-thrombin is a coagulation protein in the blood stream that has many effects in the coagulation cascade...
. Thrombin is produced from prothrombin, by the action of an enzyme, prothrombinase, in the final states of coagulation. Fibrin is then cross linked by factor XIII to form a blood clot. The principal
inhibitorEnzyme inhibitors are molecules that bind to enzymes and decrease their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
of
thrombinThrombin also commonly called pro-thrombin is a coagulation protein in the blood stream that has many effects in the coagulation cascade...
in normal blood circulation is antithrombin III. Similar to antithrombin III, the anticoagulatant activity of hirudin is based on its ability to inhibit the pro-coagulant activity of
thrombinThrombin also commonly called pro-thrombin is a coagulation protein in the blood stream that has many effects in the coagulation cascade...
.
Hirudin is the most potent natural inhibitor of thrombin. Unlike antithrombin III hirudin binds to and inhibits only the activity of thrombin forms with a specific activity on fibrinogen. Therefore, hirudin prevents or dissolves the formation of clots and
thrombiA thrombus , or blood clot, is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system...
(i.e. it has a
thrombolytic activityThrombolysis is the breakdown of blood clots by pharmacological means. It is colloquially referred to as clot busting for this reason...
), and has therapeutic value in blood coagulation disorders, in the treatment of
skinThe skin is the outer covering of the body. In humans, it is the largest organ of the integumentary system made up of multiple layers of mesodermal tissue, and guards the underlying muscles, bones, ligaments and internal organs. Skin of a different nature exists in amphibians, reptiles, birds...
hematomaA haematoma, or hematoma, is a collection of blood outside the blood vessels, generally the result of hemorrhage, or more specifically, internal bleeding....
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
heparinHeparin, a highly-sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule. It can also be used to form an inner anticoagulant surface on various experimental and medical devices such as test tubes and...
, as it does not interfere with the biological activity of other serum proteins and can also act on
complexedA multiprotein complex is a group of two or more proteins. Protein complexes are a form of quaternary structure. Proteins in a protein complex are linked by non-covalent protein-protein interactions, and different protein complexes have different degrees of stability over time...
thrombin.
It is difficult to extract large amounts of hirudin from natural sources, so a method for producing and purifying this protein using
recombinantRecombinant may refer to :* A recombinant organism - an organism that contains a different combination of alleles from either of its parents. See Recombination.* Recombinant DNA - a form of artificial DNA...
biotechnologyBiotechnology is technology based on biology, agriculture, food science, and medicine. Modern use of the term usually refers to genetic engineering as well as cell- and tissue culture technologies...
has been developed. This has led to the development and marketing of a number of hirudin based anticoagulant pharmaceutical products such as
LepirudinLepirudin is an anticoagulant which functions as a direct thrombin inhibitor.It is derived from the saliva of the medicinal leech Hirudo medicinalis....
(Refludan) , Hirudin derived from Hansenula (Thrombexx, Extrauma) and Desirudin (Revasc/Iprivask). Several other
direct thrombin inhibitorDirect thrombin inhibitors are a class of medication that act as anticoagulants by directly inhibiting the enzyme thrombin. Some are in clinical use, while others are undergoing clinical development...
s are derived chemically from hirudin.
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