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Research Article Free access | 10.1172/JCI110017

Structural Determinants of the Capacity of Heparin to Inhibit the Formation of the Human Amplification C3 Convertase

Michel D. Kazatchkine, Douglas T. Fearon, Dean D. Metcalfe, Robert D. Rosenberg, and K. Frank Austen

Institut National de la Santé et de la Recherche Medicale U 28, Hôpital Broussais, Paris, France

Departments of Medicine, Harvard Medical School, Robert B. Brigham Division of the Affiliated Hospitals Center, Inc., Beth Israel Hospital, Boston Massachusetts 02115

Sidney Farber Cancer Institute, Boston Massachusetts 02115

Find articles by Kazatchkine, M. in: JCI | PubMed | Google Scholar

Institut National de la Santé et de la Recherche Medicale U 28, Hôpital Broussais, Paris, France

Departments of Medicine, Harvard Medical School, Robert B. Brigham Division of the Affiliated Hospitals Center, Inc., Beth Israel Hospital, Boston Massachusetts 02115

Sidney Farber Cancer Institute, Boston Massachusetts 02115

Find articles by Fearon, D. in: JCI | PubMed | Google Scholar

Institut National de la Santé et de la Recherche Medicale U 28, Hôpital Broussais, Paris, France

Departments of Medicine, Harvard Medical School, Robert B. Brigham Division of the Affiliated Hospitals Center, Inc., Beth Israel Hospital, Boston Massachusetts 02115

Sidney Farber Cancer Institute, Boston Massachusetts 02115

Find articles by Metcalfe, D. in: JCI | PubMed | Google Scholar

Institut National de la Santé et de la Recherche Medicale U 28, Hôpital Broussais, Paris, France

Departments of Medicine, Harvard Medical School, Robert B. Brigham Division of the Affiliated Hospitals Center, Inc., Beth Israel Hospital, Boston Massachusetts 02115

Sidney Farber Cancer Institute, Boston Massachusetts 02115

Find articles by Rosenberg, R. in: JCI | PubMed | Google Scholar

Institut National de la Santé et de la Recherche Medicale U 28, Hôpital Broussais, Paris, France

Departments of Medicine, Harvard Medical School, Robert B. Brigham Division of the Affiliated Hospitals Center, Inc., Beth Israel Hospital, Boston Massachusetts 02115

Sidney Farber Cancer Institute, Boston Massachusetts 02115

Find articles by Austen, K. in: JCI | PubMed | Google Scholar

Published January 1, 1981 - More info

Published in Volume 67, Issue 1 on January 1, 1981
J Clin Invest. 1981;67(1):223–228. https://doi.org/10.1172/JCI110017.
© 1981 The American Society for Clinical Investigation
Published January 1, 1981 - Version history
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Abstract

The ability of heparin glycosaminoglycan to prevent formation of the properdin-stabilized amplification C3 convertase is independent of antithrombin binding activity and requires substitution of the amino sugar and a degree of oxygen (O)-sulfation which could be on the uronic acid or the amino sugar. Preparations of heparin glycosaminoglycan isolated by different techniques from different species (rat, human, and porcine) exhibited an equivalent capacity to inhibit generation of the amplification C3 convertase. Hyaluronic acid, which is devoid of O-sulfation, had no inhibitory activity; chondroitin 4-sulfate of rat and whale origins, chondroitin 6-sulfate of rat and shark origins, and dermatan sulfate from porcine skin are O-sulfated on the galactosamine and had minimal activity. Porcine heparin glycosaminoglycan, isolated on the basis of affinity for antithrombin III, had no greater anticomplementary activity than porcine glycosaminoglycan, which failed to bind antithrombin III and had essentially no anticoagulant activity. Nitrogen (N)-desulfation of porcine heparin reduced anticomplementary activity to the level of the other sulfated mucopolysaccharides, and both N-resulfation and N-acetylation restored the original activities, thereby indicating a requirement for N-substitution, but not N-sulfation. N-resulfation of N-desulfated and O-desulfated heparin did not restore any activity, thus indicating that O-sulfation and N-substitution represent independent, critical structural requirements for the anticomplementary activity of heparin glycosaminoglycan. Inasmuch as N-desulfated-N-acetylated heparin had no anticoagulant activity, the nature of the N-substitution completely distinguishes the plasma-protein effector pathway that is inhibited.

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