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Search for the heparin antithrombin III-binding site precursor.
R J Linhardt1, H M Wang, D Loganathan
1Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa, Iowa City 52242.
The Journal of Biological Chemistry
|February 5, 1992
Summary
Heparin biosynthesis
Area of Science:
- Biochemistry
- Glycoscience
- Molecular Biology
Background:
- Heparin's anticoagulant activity relies on a specific antithrombin III (ATIII) binding site.
- This site is formed by 3-O-sulfotransferase during heparin biosynthesis.
- Low ATIII affinity heparin suggests incomplete 3-O-sulfotransferase activity.
Purpose of the Study:
- Investigate the precursor to the ATIII binding site in heparin.
- Determine if low ATIII affinity is due to incomplete sulfation or earlier biosynthetic steps.
Main Methods:
- Porcine mucosal heparin was depolymerized using heparin lyase.
- Oligosaccharides were isolated and their structures determined.
- Heparin fractions with varying ATIII affinity were analyzed.
Main Results:
- A precursor oligosaccharide was identified, comprising only 0.8 mol % of the mixture.
- This precursor showed minimal enrichment in low-affinity heparin fractions.
- The precursor was only slightly depleted in high-affinity heparin fractions.
Conclusions:
- The low abundance of the identified precursor suggests it's not the sole determinant of ATIII binding affinity.
- Heparin's ATIII affinity may be primarily regulated by earlier biosynthetic steps controlling precursor site formation.
- This challenges the notion that incomplete 3-O-sulfotransferase action is the main cause of low-affinity heparin.