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Glycobiology Advance Access published online on March 19, 2004
Glycobiology, doi:10.1093/glycob/cwh057
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Submitted on November 20, 2004
Revised on January 9, 2004
Accepted on January 11, 2004

© 2004 Glycobiology © Oxford University Press 2004; all rights reserved.

ORIGINAL ARTICLES

Mapping critical biological motifs and biosynthetic pathways of heparan sulfate

Roger Lawrence 1, Balagurunathan Kuberan 1, Miroslaw Lech 1, David L. Beeler 1, and Robert D. Rosenberg 1*

1 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; Division of Molecular and Vascular Medicine, BIDMC, Harvard Medical School, Boston, MA 02215

* To whom correspondence should be addressed. E-mail: rdrrosen{at}mit.edu.

Abstract

Heparan Sulfate (HS) interacts with numerous proteins at the cell surface and orchestrates a myriad of biological events. Unraveling the mechanisms of these events at the molecular level calls for the structural analysis of these negatively charged and highly heterogeneous biopolymers. However, HS is often available only in small quantities, and the task of structural analysis necessitates the use of ultra sensitive methods, such as mass spectrometry. Sequence heterogeneity within HS chains required us to identify critical functional groups and their spacing in order to determine structure function relationships for HS. We carried out structural analysis of HS isolated from wild type, 3-OST-1, 3-OST-3A, or 3-OST-5 sulfotransferase transduced Chinese hamster ovary (CHO) cells and also from various tissues. In the context of tissue specific HS, the data allowed us to map the biosynthetic pathways responsible for the placement of critical groups. As a means of determining the distance between critical groups within a motif, we determined the spacing of the rare GlcNAc-GlcA disaccharide sequence in the completely desulfated re-N-sulfated porcine intestinal heparin. These disaccharides are biosynthetic regulatory markers for 3-OST-1 modification and the partial structure of the ATIII binding site. They occur only at the distance of hexasaccharide, octasaccharide, decasaccharide or dodecasaccharide. Thus this approach allowed us to map both the biosynthetic pathways for generating critical functional groups and their spacing within HS. Our new strategy removes two obstacles to rapid progress in this field of research.


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