Hirudin is a naturally occurring peptide in the of Hematophagy (such as Hirudo medicinalis) that has a blood anticoagulant property.
Hirudin (MEROPS I14.001) belongs to a superfamily (MEROPS IM) of protease inhibitors 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 and a C-terminal domain that is completely disordered when the protein is
protein complex 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
Serine-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
Helix loop that forms many hydrophobic contacts.
Natural hirudin contains a mixture of various
protein isoform of the protein. However,
Recombinant 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
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
Enzyme inhibitor of
thrombin 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 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 thrombus (i.e., it has a thrombolysis), and has therapeutic value in blood diseases, in the treatment of skin and of superficial , 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 protein complex 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 DNA biotechnology 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.
See also
-
Hirudotherapy
-
Discovery and development of direct thrombin inhibitors
External links
