title: Control of the heparosan N-deacetylation leads to an improved bioengineered heparin.
abstract: The production of the anticoagulant drug heparin from non-animal sources has a number of advantages over the current commercial production of heparin. These advantages include better source material availability, improved quality control, and reduced concerns about animal virus or prion impurities. A bioengineered heparin would have to be chemically and biologically equivalent to be substituted for animal-sourced heparin as a pharmaceutical. In an effort to produce bioengineered heparin that more closely resembles pharmaceutical heparin, we have investigated a key step in the process involving the N-deacetylation of heparosan. The extent of N-deacetylation directly affects the N-acetyl/N-sulfo ratio in bioengineered heparin and also impacts its molecular weight. Previous studies have demonstrated that the presence and quantity of N-acetylglucosamine in the nascent glycosaminoglycan chain, serving as the substrate for the subsequent enzymatic modifications (C5 epimerization and O-sulfonation), can impact the action of these enzymes and, thus, the content and distribution of iduronic acid and O-sulfo groups. In this study, we control the N-deacetylation of heparosan to produce a bioengineered heparin with an N-acetyl/N-sulfo ratio and molecular weight that is similar to animal-sourced pharmaceutical heparin. The structural composition and anticoagulant activity of the resultant bioengineered heparin was extensively characterized and compared to pharmaceutical heparin obtained from porcine intestinal mucosa.
authors.affiliation: Department of Biology, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Wang
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.forename: Zhenqing
authors.initials: Z
authors.lastname: Zhang
authors.forename: Mellisa
authors.initials: M
authors.lastname: Ly
authors.forename: Majde
authors.initials: M
authors.lastname: Takieddin
authors.forename: Shaker
authors.initials: S
authors.lastname: Mousa
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Dordick
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Linhardt
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism; D000925:Anticoagulants / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004187:Disaccharides / Q000737:chemistry / Q000378:metabolism*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism*; D006493:Heparin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007218:Industrial Microbiology / Q000379:methods*; D015394:Molecular Structure; D008970:Molecular Weight
chemical_list: D000925:Anticoagulants; D004187:Disaccharides; C560363:heparosan; D006493:Heparin; D000117:Acetylglucosamine