Bioengineered heparins and heparan sulfates.
Bioengineered heparins and heparan sulfates.
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DOI：
10.1016/j.addr.2015.11.002
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发表时间：
2016-02-01
影响因子：
16.1
通讯作者：
Linhardt RJ
中科院分区：
文献类型：
--
作者：
Fu L;Suflita M;Linhardt RJ
肝素和硫酸乙酰肝素是一类具有重要生物学和药理学活性的线性阴离子多糖，称为糖胺聚糖。这些多糖具有复杂的结构和多分散性，在动物细胞的高尔基体中生物合成。硫酸乙酰肝素是一种广泛分布的膜和细胞外糖胺聚糖，而肝素主要存在于肥大细胞颗粒的细胞内。虽然肝素在历史上因其抗凝血活性而受到大多数科学关注，但硫酸乙酰肝素在正常和病理生理学中的多方面作用的兴趣稳步增长。这些糖胺聚糖的化学合成在很大程度上被其结构复杂性所排除。今天，我们依靠家畜动物组织来分离和每年商业化生产数百吨肝素，用于生产抗凝药物和医疗器械涂层。动物源肝素和硫酸乙酰肝素的变异性、其固有杂质、来源组织的有限可用性、这些来源材料及其生产工艺的控制不良，表明需要新的生产方法。在过去的十年中，在这些糖胺聚糖的生物技术生产方面做出了重大努力，这是由治疗应用和作为研究其天然功能的探针驱动的。本文综述了这些糖胺聚糖在人类健康和疾病中的复杂生物学，以及重组技术在肝素和硫酸乙酰肝素的化学酶合成和代谢工程中的应用。
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.