Heavy Heparin: A Stable Isotope-Enriched, Chemoenzymatically-Synthesized, Poly-Component Drug

Angew Chem Int Ed Engl. 2019 Apr 23;58(18):5962-5966. doi: 10.1002/anie.201900768. Epub 2019 Apr 1.


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.

Keywords: chemoenzymatic synthesis; deuterated drugs; heparin; pharmacology; stable isotope labeling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anticoagulants / pharmacology
  • Anticoagulants / therapeutic use*
  • Heparin*
  • Humans
  • Rabbits


  • Anticoagulants
  • Heparin