期刊
CARBOHYDRATE POLYMERS
卷 122, 期 -, 页码 399-407出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.carbpol.2014.10.054
关键词
Bioengineered heparin; One-pot synthesis; Liquid chromatography-mass spectrometry; United States Pharmacopeia; Nuclear magnetic resonance spectroscopy
资金
- US National Institutes of Health [HL096972, HL62244, HL094463, GM38060]
- Heparin Consortium
Contamination in heparin batches during early 2008 has resulted in a significant effort to develop a safer bioengineered heparin using bacterial capsular polysaccharide heparosan and recombinant enzymes derived from the heparin/heparan sulfate biosynthetic pathway. This requires controlled chemical N-deacetylation/N-sulfonation of heparosan followed by epimerization of most of its glucuronic acid residues to iduronic acid and O-sulfation of the C2 position of iduronic acid and the C3 and C6 positions of the glucosamine residues. A combinatorial study of multi-enzyme, one-pot, in vitro biocatalytic synthesis, carried out in tandem with sensitive analytical techniques, reveals controlled structural changes leading to heparin products similar to animal-derived heparin active pharmaceutical ingredients. Liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy analysis confirms an abundance of heparin's characteristic trisulfated disaccharide, as well as 3-O-sulfo containing residues critical for heparin binding to antithrombin III and its anticoagulant activity. The bioengineered heparins prepared using this simplified one-pot chemoenzymatic synthesis also show in vitro anticoagulant activity. (C) 2014 Elsevier Ltd. All rights reserved.
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