通过利用生物合成网络,蛋白质工程和一式多酶级联来构建甲基化物
Mingju Yao1, Haotian Wang1, Zilong Wang1
1State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing, 100191, China.
Angewandte Chemie (International ed. in English)
|April 14, 2024
概括
这项研究确定了新型酶用于乙醇糖化物 (PhG) 生物合成,使多酶级联成为可能. 这种级联有效地重建了多种PhG,其中一些显示肝细胞保护.
科学领域:
- 生物催化剂是一种生物催化剂.
- 自然产品的合成自然产品的合成
- 酶学 是一种酶学.
背景情况:
- 乙基化物 (PhGs) 具有多样化的结构和药理活动.
- 传统的PhG合成具有挑战性;多酶级联提供了一个简洁的替代方案.
- 确定用于PhG生物合成的综合性酶集至关重要,但很困难.
研究的目的:
- 探索从天然前体中生物合成PhG重建.
- 为了确定参与PhG生物合成的新型酶.
- 为高效的PhG合成和多样化开发一个多酶级联.
主要方法:
- 发现和描述了12种催化酶,包括新型的甘氨基转移酶和多氧化酶.
- 确定CmGT3的晶体结构,以确定酶工程的关键残留物.
- 糖系转移酶的工程,以改变糖的供体特异性.
- 使用已识别的酶建立一个单一的多酶级联.
主要成果:
- 确定了12种催化酶,包括四种新的6'-OH糖酶转移酶和三种新的多氧化酶.
- 确定了CmGT3的晶体结构,揭示了糖供体特异性至关重要的144#残留物.
- 改造的甘氨基转移酶显示出改变了糖供体识别.
- 开发了一种单多酶级联,实现高达12.6倍的增强转化率.
- 重建了26个具有高转换率的PhG,并通过质谱检测检测了20个额外的PhG.
- 附加糖和基模块的PhGs显示出显著的肝细胞保护.
结论:
- 为 fenilethanoid glycoside 生合成提供了新的催化工具.
- 展示了各种自然产品的无细胞酶结构的概念验证.
- 突出了工程酶和多酶级联在天然产品合成中的潜力.
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