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Heavy Heparin: A Stable Isotope‐Enriched, Chemoenzymatically‐Synthesized, Poly‐Component Drug
Author(s) -
Cress Brady F.,
Bhaskar Ujjwal,
Vaidyanathan Deepika,
Williams Asher,
Cai Chao,
Liu Xinyue,
Fu Li,
MChari Vandhana,
Zhang Fuming,
Mousa Shaker A.,
Dordick Jonathan S.,
Koffas Mattheos A. G.,
Linhardt Robert J.
Publication year - 2019
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201900768
Subject(s) - sulfation , chemistry , heparin , glycosaminoglycan , anticoagulant drug , enzyme , disaccharide , epimer , biochemistry , stereochemistry
Heparin is a highly sulfated, complex polysaccharide and widely used anticoagulant pharmaceutical. In this work, we chemoenzymatically synthesized perdeuteroheparin from biosynthetically enriched heparosan precursor obtained from microbial culture in deuterated medium. Chemical de‐ N ‐acetylation, chemical N ‐sulfation, enzymatic epimerization, and enzymatic sulfation with recombinant heparin biosynthetic enzymes afforded perdeuteroheparin comparable to pharmaceutical heparin. A series of applications for heavy heparin and its heavy biosynthetic intermediates are demonstrated, including generation of stable isotope labeled disaccharide standards, development of a non‐radioactive NMR assay for glucuronosyl‐C5‐epimerase, and background‐free quantification of in vivo half‐life following administration to rabbits. We anticipate that this approach can be extended to produce other isotope‐enriched glycosaminoglycans.