Control of the heparosan N-deacetylation leads to an improved bioengineered heparin.
Control of the heparosan N-deacetylation leads to an improved bioengineered heparin.
复制标题
DOI：
10.1007/s00253-011-3231-5
复制
发表时间：
2011-07
影响因子：
5
通讯作者：
Linhardt, Robert J.
中科院分区：
文献类型：
--
作者：
Wang, Zhenyu;Yang, Bo;Zhang, Zhenqing;Ly, Mellisa;Takieddin, Majde;Mousa, Shaker;Liu, Jian;Dordick, Jonathan S.;Linhardt, Robert J.
与目前肝素的商业化生产相比，从非动物来源生产抗凝药物肝素具有许多优势。这些优势包括更好的原材料可用性、改进的质量控制以及减少对动物病毒或朊病毒杂质的担忧。生物工程肝素必须在化学和生物学上等效才能替代动物源肝素作为药物。为了生产更类似于药用肝素的生物工程肝素，我们研究了涉及肝素 N-脱乙酰化过程中的关键步骤。 N-脱乙酰化的程度直接影响生物工程肝素中N-乙酰基/N-磺基的比例，也影响其分子量。先前的研究表明，新生糖胺聚糖链中 N-乙酰氨基葡萄糖的存在和数量，作为后续酶促修饰（C5 差向异构化和 O-磺化）的底物，可以影响这些酶的作用，从而影响艾杜糖醛酸和 O-磺基的含量和分布。在这项研究中，我们控制heparosan的N-脱乙酰化来生产生物工程肝素，其N-乙酰基/N-磺基比例和分子量与动物源药物肝素相似。对所得生物工程肝素的结构组成和抗凝血活性进行了广泛的表征，并与从猪肠粘膜获得的药用肝素进行了比较。
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.
登录
查看更多内容
影响因子：
4.3
作者：
Ly, Mellisa;Wang, Zhenyu;Laremore, Tatiana N.;Zhang, Fuming;Zhong, Weihong;Pu, Dennis;Zagorevski, Dmitri V.;Dordick, Jonathan S.;Linhardt, Robert J.
通讯作者：
Linhardt, Robert J.
影响因子：
46.9
作者：
Guerrini, Marco;Beccati, Daniela;Sasisekharan, Ram
通讯作者：
Sasisekharan, Ram
影响因子：
4.3
作者：
Cesaretti, M;Luppi, E;Volpi, N
通讯作者：
Volpi, N
影响因子：
7.4
作者：
Korir, Albert K.;Lirntiaco, John F. K.;Larive, Cynthia K.
通讯作者：
Larive, Cynthia K.
影响因子：
4.8
作者：
Li, JP;HagnerMcWhirter, A;Lindahl, U
通讯作者：
Lindahl, U