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作为14-3-3蛋白质-蛋白质相互作用稳定剂的cotylenin二二烯糖化物的总生物合成

Zhenhua Guan¹, Nanyu Yao¹, Wenling Yuan¹

¹Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, Tongji Medical College, Huazhong University of Science and Technology Wuhan 430030 Hubei Province People's Republic of China zhangyh@mails.tjmu.edu.cn ying_ye@hust.edu.cn.

Chemical science

|December 9, 2024

概括

研究人员阐明了cotylenins (CNs) 的生物合成途径,这是具有治疗潜力的真菌二烯基糖化物. 这一突破使未来药物开发的总生物合成和结构多样化成为可能.

科学领域:

自然产品生物合成自然产品生物合成
化学生物学化学生物学
药物发现药物发现药物发现

背景情况:

科提莱宁 (CNs) 是一种具有治疗潜力的真菌二烯基糖化物,由于它们的14-3-3蛋白-蛋白相互作用 (PPI) 稳定活性,它们具有治疗潜力.
自1970年发现CNs以来,其生物合成途径一直难以捉摸,这限制了它们的可用性和研究.

研究的目的:

为了确定CNs的生物合成基因集群.
为了阐明CNs的完整生物合成途径.
为了实现总生物合成,并探索CNs的结构多样化.

主要方法:

"cty"生物合成基因集群的识别.
酶功能的解,包括甘氨基转移酶,甲基转移酶,前转移酶和P450 (CtyA).
对于CN中间体和新衍生物的总生物合成的异质表达式.

主要成果:

确定了"cty"基因和CN生物合成途径.
描述了参与糖部分组装,修饰和氧化的关键酶.
通过异质表达实现了CN中间体 (CN-C,E,F,I) 和新型衍生物的总生物合成.
途径中间体表现出14-3-3 PPI稳定,突出显示了糖化物修饰的作用.

结论:

阐明的途径和识别的酶为合理合成cotylenin A和衍生物提供了基础.
路径酶是扩大二糖化物结构多样性的宝贵工具.
了解CN生物合成为针对14-3-3 PPI的新型治疗剂开辟了道路.

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