An investigation of nitrile transforming enzymes in the chemo-enzymatic synthesis of the taxol sidechain.
An investigation of nitrile transforming enzymes in the chemo-enzymatic synthesis of the taxol sidechain.
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DOI：
10.1039/c5ob01191d
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发表时间：
2015-07
影响因子：
3.2
通讯作者：
B. Wilding;A. B. Veselá;J. Perry;G. Black;Meng Zhang;L. Martínková;N. Klempier
中科院分区：
文献类型：
--
作者：
B. Wilding;A. B. Veselá;J. Perry;G. Black;Meng Zhang;L. Martínková;N. Klempier
紫杉醇是一种广泛用于治疗癌症的抗微管剂。紫杉醇是通过将N-苯甲酰基-（2 R，3S）-3-苯基异丝氨酸侧链偶联到浆果赤霉素III核心结构上的半合成路线制备的。紫杉醇侧链的前体先前已经在化学酶促方法中使用酰基化酶、脂肪酶和还原酶制备，其主要特征在于反应途径中的对映选择性酶促步骤早期。在这里，研究了腈水解酶（即腈水合酶和腈酶）对两种不同侧链前体的酶促水解。两种侧链前体，开链α-羟基-β-氨基腈和氰基二氢恶唑，都适合在酶促步骤后直接偶联至浆果赤霉素III。针对腈水解酶和腈水合酶在水解两种紫杉醇侧链前体及其差向异构体中的活性和选择性，筛选了广泛的腈水解酶和腈水合酶。许多腈水解酶和腈水合酶转化侧链前体和它们的差向异构体。
Paclitaxel (taxol) is an antimicrotubule agent widely used in the treatment of cancer. Taxol is prepared in a semisynthetic route by coupling the N-benzoyl-(2R,3S)-3-phenylisoserine sidechain to the baccatin III core structure. Precursors of the taxol sidechain have previously been prepared in chemoenzymatic approaches using acylases, lipases, and reductases, mostly featuring the enantioselective, enzymatic step early in the reaction pathway. Here, nitrile hydrolysing enzymes, namely nitrile hydratases and nitrilases, are investigated for the enzymatic hydrolysis of two different sidechain precursors. Both sidechain precursors, an openchain α-hydroxy-β-amino nitrile and a cyanodihydrooxazole, are suitable for coupling to baccatin III directly after the enzymatic step. An extensive set of nitrilases and nitrile hydratases was screened towards their activity and selectivity in the hydrolysis of two taxol sidechain precursors and their epimers. A number of nitrilases and nitrile hydratases converted both sidechain precursors and their epimers.