Enzymatic synthesis of glycosaminoglycan heparin.
Heparin and its low molecular weight heparin derivatives, widely used as clinical anticoagulants, are acidic polysaccharide members of a family of biomacromolecules called glycosaminoglycans (GAGs). Heparin and the related heparan sulfate are biosynthesized in the Golgi apparatus of eukaryotic cells. Heparin is a polycomponent drug that currently is prepared for clinical use by extraction from animal tissues. A heparin pentasaccharide, fondaparinux, has also been prepared through chemical synthesis for use as a homogenous anticoagulant drug. Recent enabling technologies suggest that it may now be possible to synthesize heparin and its derivatives enzymatically. Moreover, new technologies including advances in synthetic carbohydrate synthesis, enzyme-based GAG synthesis, micro- and nano-display of GAGs, rapid on-line structural analysis, and microarray/microfluidic technologies might be applied to the enzymatic synthesis of heparins with defined structures and exhibiting selected activities. The advent of these new technologies also makes it possible to consider the construction of an artificial Golgi to increase our understanding of the cellular control of GAG biosyntheses in this organelle.
Linhardt
Robert J
RJ
Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA. linhar@rpi.edu
Dordick
Jonathan S
JS
Deangelis
Paul L
PL
Liu
Jian
J
D000818:Animals; D000925:Anticoagulants / Q000378:metabolism*; D002474:Cell-Free System / Q000201:enzymology; D000077425:Fondaparinux; D006025:Glycosaminoglycans / Q000096:biosynthesis*; D006056:Golgi Apparatus / Q000201:enzymology*; D006493:Heparin / Q000096:biosynthesis*; D011134:Polysaccharides / Q000096:biosynthesis*
D000925:Anticoagulants; D006025:Glycosaminoglycans; D011134:Polysaccharides; C020341:glucosaminoglycans; D006493:Heparin; D000077425:Fondaparinux