Angewandte Chemie International Edition

Cover image for Vol. 54 Issue 32

Editor: Peter Gölitz, Deputy Editors: Neville Compton, Haymo Ross

Online ISSN: 1521-3773

Associated Title(s): Angewandte Chemie, Chemistry - A European Journal, Chemistry – An Asian Journal, ChemistryOpen, ChemPlusChem, Zeitschrift für Chemie

For full article and contact information, see Angew. Chem. Int. Ed. 2001, 40 (9), 1670-1673

No. 09/2001

A Twisted Boat fights Thrombosis

The unusual structure of one sugar unit
is crucial to the effectiveness
of heparin in preventing thrombosis

Heparin ointment is often found in medicine cabinets for use on minor sport injuries such as bruises. However, heparin is most important in operations and blood transfusions, where it is used to prevent thromboses and embolisms. Heparin is a substance produced by the body itself to hamper blood clotting. It increases the effectiveness of antithrombin, which is an inhibitor of human blood clotting factors. Heparin is a polysaccharide, which means that it is made up of a long chain of sugar units. A specific sequence of five sugars plays a crucial role in the activity of heparin; it binds to antithrombin. French researchers working with Pierre Sinaÿ and Maurice Petitou have now made an important contribution to completing the whole picture.

The backbone of each of the sugar units is a flexible six-membered ring made of one oxygen and five carbon atoms. This ring is most stable in a conformation called the chair formation, which can be envisioned by picturing a planar hexagon and then folding one vertex up to form the "back-rest" and folding the opposite vertex down - like the footrest of a comfortable recliner. This leaves a rectangle surface to act as the "seat". Within the polysaccharide chain the chair can be oriented in different ways, depending on which vertex is folded up or down.

One of the units in heparin's crucial five-sugar chain, a unit of iduronic acid, seems to go its own way, preferring to adopt a different, unusual conformation. Again starting from the imaginary planar hexagon, in this case both vertices are folded up - like the bow and stern of a boat. Additionally, the square "hull" of the boat is twisted. Hence the name of this conformation: "skew-boat". Is this unusual iduronic acid important for binding to antithrombin? Flexible as sugars are, it is impossible to separate the different conformers from each other and to examine them separately, because they can constantly interchange.

The researchers thus resorted to a trick; they synthesized three variations of the five-sugar chain. The vertices of the iduronic acid hexagon were either bridged or equipped with a voluminous appendage in order to fix them in three different conformations: two chairs and the twist-boat. It turns out that only the pentasaccharide containing the iduronic acid in the twist-boat conformation binds to antithrombin. "This clearly proves that when binding to antithrombin, the iduronic acid moiety is present in this unusual conformation," say Sinaÿ and Petitou. This knowledge opens up new possibilities for the design of heparin analogs.