教授
天然产物是新药研发的重要源泉，但其成药潜力高度依赖于结构优化。复杂天然产物的碳骨架由于化学性质惰性，选择性的结构修饰极具挑战，而罕有实现；在药物生产方面，一些非微生物来源的天然药物，常需通过天然提取，或者高难度的全合成方法进行制造，生产效率低下且成本高昂。因此，如何开发普适、高效的骨架修饰与合成方法，是化学领域的难点和热点，亦是当前药物在研发和生产两端有待解决的瓶颈。本实验室长期致力于天然产物骨架的高效构建和选择性修饰这一科学问题，一方面从解析聚酮合酶体系催化合成、组装和环合碳链的核心分子机制出发，利用酶工程和合成生物学等手段对聚酮合酶催化合成碳链过程进行精准操控，来实现对聚酮、生物碱等重要天然产物的定向生物合成以及骨架结构的精准修饰（Bottom-UP策略）；另一方面采用Top-Down策略，从解析植物甾醇的生物降解机制出发，通过工程化手段精准控制微生物降解植物甾醇和修饰甾体骨架的过程，以廉价的植物甾醇为原料进行甾体药物的高效合成和创新。通过生物合成与化学合成结合的方式，发展针对各类天然产物骨架的普适、高效的合成与编辑策略，用于拓展结构多样性和提高药物的生产效率，实现对天然产物资源的深度开发及天然药物的高效创制。
Xiaoli Yan, Xinying Jia, Zhenyao Luo, Shunjia Ji, Meng-Jie Zhang, Hui Zhang, Mingjia Yu, Julie Orts, Kai Jiang, Zhi Lin, Zixin Deng, Xu-Dong Kong, Bostjan Kobe, Yi-Lei Zhao, Mehdi Mobli, Xudong Qu
An enzymatic dual-oxa Diels-Alder reaction constructs the oxygen-bridged tricyclic acetal unit of (-)-anthrabenzoxocinones.
Nature Chemistry 2024, accepted.
Guangzheng Wei, Borui Duan, Tai-Ping Zhou, Wenya Tian, Chenghai Sun, Zhi Lin, Zixin Deng, Binju Wang, Zhengyu Zhang, Xudong Qu.
A Nucleobase-driven P450 peroxidase system enables regio- and stereo-specific formation of C‒C and C‒N bonds.
Proceedings of the National Academy of Sciences of the United States of America 2024, 121, e2412890121.
Kai Jiang, Xu Chen, Xiaoli Yan, Zixin Deng, Shunkun Luo, Xudong Qu. An unusual aromatase/cyclase programs the formation of the phenyldimethylanthrone framework in anthrabenzoxocinones and fasamycin.
Proceedings of the National Academy of Sciences of the United States of America 2024, 121, e2321722121.
Fuzheng Song, Mengmeng Zheng, Junlin Wang, Huanhuan Liu, Zhi Lin, Bengbeng Liu, Zixin Deng, Qianghui Zhou, Xudong Qu. A chemoenzymatic approach to C14-functionalized steroids.
Nature Synthesis 2023, 2, 729-739.
Zhi Lin, Zhiwei Hu, Linjun Zhou, Benben Liu, Xiaowei Huang, Zixin Deng, Xudong Qu.
A large conserved family of small-molecule carboxyl methyltransferases identified from microorganisms.
Proceedings of the National Academy of Sciences of the United States of America, 2023, 120, e2301389120.
Chenghai Sun, Bao-Di Ma, Guangjun Li, Wenya Tian, Lu Yang, Haidong Peng, Zhi Lin, Zixin Deng, Xu-Dong Kong, Xudong Qu.
Engineering the substrate specificity of a P450 dimerase enables the collective biosynthesis of heterodimeric tryptophan-containing diketopiperazines.
Angewandte Chemie International Edition 2023, 62, e202304994.
Xiaoli Yan, Jun Zhang, Hongqun Tan, Zhihao Liu, Kai Jiang, Wenya Tian, Mengmeng Zheng, Zhi Lin, Zixin Deng, Xudong Qu. A pair of atypical KAS III homologues with initiation and elongation functions programs the polyketide biosynthesis in asukamycin.
Angewandte Chemie International Edition 2022, e202200879
Mengmeng Zheng, Jun Zhang, Wan Zhang, Lu Yang, Xiaoli Yan, Wenya Tian, Zhihao Liu, Zhi Lin, Zixin Deng, Xudong Qu. An atypical acyl-CoA synthetase enables efficient biosynthesis of extender units for engineering a polyketide carbon scaffold.
Angewandte Chemie International Edition 2022, e202208734..
Haidong Peng, Yaya Wang, Yanan Zhang, Zixing Deng, Zhenghua Tian, Xudong Qu.
A dual role reductase from phytosterol catabolism enables efficient production of valuable
steroid precursors.
Angewandte Chemie International Edition 2021, 60, 5414-5420.
Chenghai Sun, Zhenyao Luo (co-first author), Wenlu Zhang, Wenya Tian, Haidong Peng, Zhi Lin, Xiaoli Yan, Yanan Zhang, Zixin Deng, Bostjan Kobe, Xinying Jia, Xudong Qu.
Molecular basis of regio- and stereo-specificity in biosynthesis of bacterial heterodimeric ketopiperazines.
Nature Communications 2020, 11, 6251.
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