Chemo-Enzymatic Synthesis of Bioactive Carbazole Derivatives
Chemo-Enzymatic Synthesis of Bioactive Carbazole Derivatives
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DOI：
10.3390/synbio2010002
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发表时间：
2024-01
期刊：
影响因子：
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通讯作者：
Saad Alrashdi;Federica Casolari;K. Kyeremeh;Hai Deng
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文献类型：
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作者：
Saad Alrashdi;Federica Casolari;K. Kyeremeh;Hai Deng
咔唑是抗微生物/抗病毒生物碱天然产物或治疗剂的关键支架。因此，获得结构多样的含吲哚的咔唑已经引起了相当大的关注。在这份报告中，一个试点研究描述了使用生物转化，以提供咔唑，含有各种酰基取代基。生物转化系统包含硫胺素-二磷酸（ThDP）依赖性酶NzsH、FabH样3-酮脂酰-ACP合酶NzsJ和芳香酶/环化酶NzsI，编码于细菌咔唑生物碱天然产物（名为neocarazostatin A）的生物合成基因簇（nzs）中。在设计的生物转化系统中利用一系列酰基-SNAC（天然底物的合成酰基-硫酯类似物）以及吲哚-3-丙酮酸和丙酮酸允许生产咔唑衍生物。我们的研究结果表明，这三个酶系统显示出相当大的基板配置文件对酰基供体生产的咔唑与不同的酰基取代基。最后，在生物转化系统中还包括另外两种酶：色氨酸合成酶独立β亚基变体PfTrpB（由文献中的定向进化产生）和市售L-氨基酸氧化酶（LAAO）。这两种酶的添加允许转化以吲哚结构单元开始，以提供在吲哚环系统中具有修饰的咔唑。
Carbazoles are key scaffolds of either antimicrobial/antiviral alkaloid natural products or therapeutics. As such, access to structurally diverse indole-containing carbazoles has attracted considerable attention. In this report, a pilot study is described using biotransformation to provide carbazoles that contain various acyl substituents. The biotransformation system contains the thiamine-diphosphate (ThDP)-dependent enzyme NzsH, the FabH-like 3-ketoacyl-ACP synthase NzsJ, and the aromatase/cyclase NzsI, encoded in the biosynthetic gene cluster (nzs) of the bacterial carbazole alkaloid natural product named neocarazostatin A. The utilization of a range of acyl-SNACs (synthetic acyl-thioester analogues of the native substrate) together with indole-3-pyruvate and pyruvate in the designed biotransformation system allows production of carbazole derivatives. Our results demonstrate that this three-enzyme system displays a considerable substrate profile toward acyl donors for production of carbazoles with different acyl substituents. Finally, two more enzymes were included in the biotransformation system: the tryptophan synthase stand-alone β-subunit variant, PfTrpB, generated from directed evolution in the literature, and a commercially available L-amino acid oxidase (LAAO). The addition of these two enzymes allows the transformation to start with indole building blocks to provide carbazoles with modifications in the indole ring system.