Hirudin, the most potent natural thrombin inhibitor identified to date, is a 65-amino-acid polypeptide (molecular mass, approximately 7 kDa) produced by the parapharyngeal glands of the medicinal leech, Hirudo medicinalis. The NH2-terminal part of the molecule (residues 1-39) is stabilized by three disulfide bridges integral to its function. The COOH-terminal moiety (residues 40-65) is highly acidic. In the 3D structure of hirudin (Clore et al., 1987; Sukumaran et al., 1987), three areas are distinguished: a central core (residues 3-30, 37-46, 56-57), a "finger" (residues 3136), and a loop (residues 47-55). Hirudin is very stable at extremes of pH (1.5-13.0) and at high temperatures (up to 90°C). It is soluble in water but insoluble in alcohol or acetone. The isoelectric point of hirudin is approximately 4.

Hirudins for therapeutic use are now produced by recombinant biotechnology, using the yeast Saccharomyces cerevisiae, yielding recombinant hirudin (r-hirudin). Lepirudin, a desulfatohirudin, differs from natural hirudin by lacking the sulfate group at Tyr-63 and also has an NH2-terminal leucine residue in place of the isoleucine. Although such structural differences result in a 10-fold reduction in the dissociation constant of r-hirudin, as compared with natural hirudin, r-hirudins remain highly selective inhibitors of thrombin, with an inhibition constant for thrombin in the picomolar range (Stone and Hofsteenge, 1986).

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