Enzymatic routes for the synthesis of ursodeoxycholic acid
Enzymatic routes for the synthesis of ursodeoxycholic acid
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DOI：
10.1016/j.jbiotec.2014.08.006
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发表时间：
2014-12-10
影响因子：
4.1
通讯作者：
Hummel, Werner
中科院分区：
文献类型：
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作者：
Eggert, Thorsten;Bakonyi, Daniel;Hummel, Werner
熊去氧胆酸是一种二级胆汁酸，用作治疗各种肝脏疾病的药物，最佳剂量为8-10 mg/kg/天。对于工业合成，这种胆汁酸的结构复杂性需要使用适当的起始材料以及应用区域选择性和对映选择性酶进行衍生化。大多数合成策略从胆酸或鹅去氧胆酸开始。后者需要将C-7位的羟基从α位转化为β位，以获得熊去氧胆酸。另一方面，胆酸不仅需要在C-7处进行相同的差向异构化反应，而且还需要除去C-12处的羟基。有几种细菌区域选择性和对映体选择性羟基类固醇脱氢酶（HSDH）来进行所需的反应，例如来自梭菌属、拟杆菌属或黄单胞菌属菌株的7 α-HSDH，来自梭菌属、科林氏菌属或瘤胃球菌属的7 β-HSDH，或来自梭菌属或来自埃格特氏菌属的12 α-HSDH。然而，所有这些生物转化反应都需要额外的步骤来再生辅酶。本文综述了熊去氧胆酸合成的多步反应体系。(C)2014爱思唯尔有限公司版权所有。
Ursodeoxycholic acid, a secondary bile acid, is used as a drug for the treatment of various liver diseases, the optimal dose comprises the range of 8-10 mg/kg/day. For industrial syntheses, the structural complexity of this bile acid requires the use of an appropriate starting material as well as the application of regio- and enantioselective enzymes for its derivatization. Most strategies for the synthesis start from cholic acid or chenodeoxycholic acid. The latter requires the conversion of the hydroxyl group at C-7 from alpha-into beta-position in order to obtain ursodeoxycholic acid. Cholic acid on the other hand does not only require the same epimerization reaction at C-7 but the removal of the hydroxyl group at C-12 as well. There are several bacterial regio- and enantio-selective hydroxysteroid dehydrogenases (HSDHs) to carry out the desired reactions, for example 7 alpha-HSDHs from strains of Clostridium, Bacteroides or Xanthomonas, 7 beta-HSDHs from Clostridium, Collinsella, or Ruminococcus, or 12 alpha-HSDH from Clostridium or from Eggerthella. However, all these bioconversion reactions need additional steps for the regeneration of the coenzymes. Selected multi-step reaction systems for the synthesis of ursodeoxycholic acid are presented in this review. (C) 2014 Elsevier B.V. All rights reserved.