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Heparin and Hirudin

Dateline: 08/07/00

By Alan Bruzel

Origins of Heparin and Hirudin

These are anticoagulant drugs, each originally isolated from natural sources: heparin from liver (hence its name), and hirudin from the medicinal leech, Hirudo medicinalis. Today, the inner lining of the small intestine of pigs provides the raw material for heparin manufacture. The hirudin gene has been cloned; thus biotechnology, not a leech farm, is the source of hirudin.

Biochemistry of Heparin and Hirudin

The paragraph above provides a hint as to how these bioactive substances differ. Hirudin has been cloned; heparin has not.

In cloning, one places a foreign gene into a host organism, usually a bacterial cell. The host organism grows and reproduces and, most importantly, replicates the foreign gene so that each of its descendants (and their descendants, and so on) receives a copy of the foreign gene. Feeding a specific inducer to these host organisms stimulates the foreign gene to direct the synthesis of its particular product (in this case, a protein), which is then purified and marketed.

Recombinant DNA technology is able to prepare hirudin because hirudin is a single protein originating from a single gene. Heparin, however, is a complex carbohydrate, and its synthesis requires the precisely ordered activities of many genes, a technique presently beyond the reach of biotechnology enterprises.

Heparin is built from alternating amino sugars and sugar acids that have varying degrees of sulfation. The following diagram illustrates only a portion of the heparin molecule. Natural heparin contains polymer chains ranging in size from 3000 up to 100,000 daltons.

Heparin (The pentasaccharide region that binds antithrombin III is shown.)

Hirudin is a smaller molecule than heparin, having 65 amino acids and a size of approximately 7000 daltons. Its hydrophobic amino (NH₂) end is constrained by intramolecular disulfide bridges; the carboxy (COOH) end of the molecule is more hydrophilic.

Hirudin (The variant HV-1 is shown.)

Heparin and Hirudin Prevent Blood Clotting

Each of these molecules prevents a blood protein, thrombin, from cleaving fibrinogen to fibrin. (Clots are formed when fibrin monomers polymerize. By interfering with the activity of thrombin, one stops blood clots from forming.) Hirudin binds directly to thrombin and inactivates it. Heparin takes a more roundabout approach by binding to another blood protein, antithrombin III. The heparin-antithrombin III complex then binds strongly to thrombin, inactivating it.

What the Web Has to Say about:
Heparin and Hirudin

Antithrombotic Therapy
Strategies for patient treatment. From Thomas G. DeLoughery, Oregon Health Sciences University.

Celsus Laboratories
Makers of a wide range of heparin products.

Feinchemie GmbH Sebnitz
Manufacturers of hirudin for laboratory use.

Guide to Anticoagulant Therapy Part 1: Heparin
Properties and uses of this anticoagulant. From Jack Hirsh and Valentin Fuster, American Heart Association.

Hemostasis and Thrombosis Center
Information on heparin and hirudin from the University of California at San Francisco.

Heparan sulfate and heparin
A chapter from the lecture material: Structure and Analysis of Proteoglycans and Hyaluronan. From the University of Kuopio.

Heparinization
Uses of heparin in coating medical devices. From David Grubb, Cornell University.

Hirudin
Student report of the structure and function of this protein. From Jeska von der Nuell, Lancaster University.

Neoparin Inc.
Suppliers of heparin and heparin derivatives.

Pork By-Products
Source of a variety of important biochemicals, including heparin. Article by John R. Romans et al.

Review of the Pharmacology, Clinical Applications, and Toxicology of Hirudin and Hirulog
Antithrombotic activities of hirudin and the synthetic peptide, hirulog. From Robert Hand et al. in Transgenica: Topics in Clinical Biotechnology.

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