Bioengineered heparins and heparan sulfates

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• 作者：Li Fu^a ; ^b ; Matthew Suflita^a ; Robert J. Linhardt^a ; ^b ; ^c ; ^d ;
• 关键词：Heparin ; Heparan sulfate ; Chemoenzymatic synthesis ; Metabolic engineering ; Glycosaminoglycans ; Sulfotransferases ; Glycosyltransferases ; 3&prime ; -Phosphoadenosine-5&prime ; -phosphosulfate
• 刊名：Advanced Drug Delivery Reviews
• 出版年：2016
• 出版时间：1 February 2016
• 年：2016
• 卷：97
• 期：Complete
• 页码：237-249
• 全文大小：2089 K

文摘

Heparin and heparan sulfates are closely related linear anionic polysaccharides, called glycosaminoglycans, which exhibit a number of important biological and pharmacological activities. These polysaccharides, having complex structures and polydispersity, are biosynthesized in the Golgi of animal cells. While heparan sulfate is a widely distributed membrane and extracellular glycosaminoglycan, heparin is found primarily intracellularly in the granules of mast cells. While heparin has historically received most of the scientific attention for its anticoagulant activity, interest has steadily grown in the multi-faceted role heparan sulfate plays in normal and pathophysiology. The chemical synthesis of these glycosaminoglycans is largely precluded by their structural complexity. Today, we depend on livestock animal tissues for the isolation and the annual commercial production of hundred ton quantities of heparin used in the manufacture of anticoagulant drugs and medical device coatings. The variability of animal-sourced heparin and heparan sulfates, their inherent impurities, the limited availability of source tissues, the poor control of these source materials and their manufacturing processes, suggest a need for new approaches for their production. Over the past decade there have been major efforts in the biotechnological production of these glycosaminoglycans, driven by both therapeutic applications and as probes to study their natural functions. This review focuses on the complex biology of these glycosaminoglycans in human health and disease, and the use of recombinant technology in the chemoenzymatic synthesis and metabolic engineering of heparin and heparan sulfates.