'Heparin'--from anticoagulant drug into the new biology

Abstract

This overview attempts to cover, from a personal viewpoint, the development of the 'heparin' field during the last four decades. In particular, it emphasizes the metamorphosis of heparan sulfate (HS), from a disturbing contaminant in heparin production to the present-day key player in cell and developmental biology. Our understanding of the structural properties of the polysaccharides has been greatly promoted by studies of their biosynthesis. We now have a fairly detailed view of the various enzymatic reactions, that convert the initial [4GlcAbeta1-4GlcNAcalpha1-]n polymer into sulfated products with highly variable proportions of GlcA/IdoA and of N-acetyl, N-sulfate and O-sulfate substituents. It is also recognized that the variously substituted domains of the polysaccharide serve to interact, in more or less specific fashion, with a multitude of proteins, and that these interactions are essential to the biological functions of the proteins. Molecular genetics has unravelled the gene structures for almost all of the enzymes required to synthesize a heparin or HS chain, and has shown that several of these proteins exhibit genetic polymorphism. While differences in substrate specificity between enzyme isoforms may help to explain the structural variability of, in particular, HS chains, we still only partly understand the key features of heparin/HS biosynthesis and its regulation.