Heavy Heparin: A Stable Isotope‐Enriched, Chemoenzymatically‐Synthesized, Poly‐Component Drug
Year: 2019
Type: article
Abstract: 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.
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
Awards: An Automated Platform for the CE-MS Analysis of Glycosaminoglycans, EAGER: Systematic Approach to Improve Probability of Metabolic Engineering Success, GOALI: Rewiring Escherichia coli for the efficient synthesis of chondroitin polysaccharides, In vitro synthesis of recombinant heparan sulfate, Endothelial glycocalyx reconstitution during sepsis
OpenAlex ID: W2922468466