Heavy heparin: A stable isotope-enriched, chemoenzymatically-synthesized, poly-component drug

Cress, Brady F.
Bhaskar, Ujjwal
Vaidyanathan, Deepika
Williams, Asher
Cai, Chao
Liu, Xinyue
Fu, Li
M-Chari, Vandhana
Zhang, Fuming
Mousa, Shaker A.
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Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
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Heavy heparin: A stable isotope-enriched, chemoenzymatically-synthesized, poly-component drug, B. F. Cress, U. Bhaskar, D. Vaidyanathan, A. Williams, C. Cai, X. Liu, L. Fu, V. M-Chari, F. Zhang, S. A. Mousa, J. S. Dordick, M. A. G. Koffas, R. J. Linhardt, Angewandte Chemie, 58, 5962 –5966, 2019.
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.
Angewandte Chemie, 58, 5962 –5966
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The Linhardt Research Labs.
The Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS)
The Linhardt Research Labs Online Collection
Rensselaer Polytechnic Institute, Troy, NY
Angewandte Chemie - International Edition
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