Structure of the antithrombin-binding site in heparin

Area of Science:

• Biochemistry
• Glycobiology
• Pharmacology

Background:

• Heparin is a complex polysaccharide known for its anticoagulant properties.
• Heparin's interaction with antithrombin is key to its therapeutic effects.
• Heparin preparations vary in composition and biological activity.

Purpose of the Study:

• To investigate the structural basis of heparin's anticoagulant activity.
• To identify specific heparin components responsible for high-affinity binding to antithrombin.
• To elucidate the role of nonsulfated L-iduronic acid in heparin's function.

Main Methods:

• Chromatographic separation of heparin fractions based on antithrombin affinity.
• Enzymatic and chemical degradation of heparin to isolate antithrombin-binding fragments.
• Compositional analysis using radiolabeling and deamination techniques.
• Periodate oxidation to determine the location of specific residues.

Main Results:

• High-affinity heparin fractions exhibited higher levels of nonsulfated L-iduronic acid compared to low-affinity fractions.
• Nonsulfated L-iduronic acid was concentrated in the antithrombin-binding regions of high-affinity heparin.
• Approximately one residue of nonsulfated L-iduronic acid was found per antithrombin-binding site.
• The location of nonsulfated L-iduronic acid within the antithrombin-binding site was determined.

Conclusions:

• Nonsulfated L-iduronic acid is essential for the anticoagulant activity of heparin.
• This specific uronic acid residue plays a critical role in the high-affinity interaction between heparin and antithrombin.
• Proposed tentative structures for antithrombin-binding sequences in heparin, highlighting the significance of nonsulfated L-iduronic acid.