Pharmaceuticals are indispensable for human survival, but there has been a long-term inssued bottleneck at both ends of drug development and production, that is, the efficient synthesis and engineering of the carbon scaffold. Structural modification is pivotal for development of natural products-derived drugs (NPD drugs). It is known that about 90% of NPD drugs have been structurally optimized. However, due to the limitation of chemical reactivity, chemical modification is usually only applicable to active functional groups (such as hydroxyl, amino, etc.), and rarely to the scaffold part composed of saturated carbon atoms (inert scaffold). Therefore, the inert carbon scaffold, which accounts for around half of the molecular scaffold, has always been a forbidden area for the development of new drugs. Hence, developing efficient and universal modification approaches to engineer them in natural products is of great significance to the development of NPD drugs. In drug production, chiral chemical catalysts are usually very expensive and difficult to be used in large-scale production, so current pharmaceutical industry still mainly relies on chiral resolution to obtain chiral drugs. This process is uneconomical, unsustainable and easy to form wastes, therefore development of efficient biosynthetic approaches to stereo-specifically making chiral carbon scaffolds is of great significance for industrial production of pharmaceuticals. The research direction of our group is 'biosynthesis of inert molecular scaffolds'. We focus on three important scaffold types, including polyketides, steroids and azacycles which constitute nearly 100,000 natural products and more than 1500 clinical drugs. Our aim is to i) understand the formation of these molecular scaffolds in natural products, and ii) to develop efficient and universal biosynthetic approaches to engineer or synthesis of these scaffolds. With our efforts, we wish to solve this long-standing bottleneck in the drug development and production.
Haidong Peng, Yaya Wang, Yanan Zhang, Zixing Deng, Zhenghua Tian, Xudong Qu*.
A dual role reductase from phytosterol catabolism enables efficient production of valuable
Angewandte Chemie International Edition 2020 DOI: 10.1002/anie.202015462
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 DOI: 10.1038/s41467-020-20022-5.
Lu Yang, Jinmei Zhu, Chenghai Sun, Zixin Deng, Xudong Qu*.
Biosynthesis of plant tetrahydroisoquinolines alkaloids through an imine reductase route.
Chemical Science 2020, 11, 364-371 (2019 Chemical Science HOT Article Collection).
Hongqun Tan, Xuejun Yang, Qi Dai, Zixin Deng, and Xudong Qu*. Unravelling the biosynthetic flexibility of UK-2A enables enzymatic synthesis of its structural variants.
ACS Synthetic Biology 2019, 8, 2659-2665.
Wenya Tian, Chenghai Sun (co-first author), Mei Zheng, Mingjia Yu, Yanan Zhang, Haidong Peng, Dongqing Zhu, Jeffery Harmer, Zixin Deng, Shilu Chen, Mohedi Mobli, Xinying Jia*, Xudong Qu*.
Efficient biosynthesis of heterodimeric C3-aryl pyrroloindoline alkaloids.
Nature Communications 2018, 9, 4428.
Yuan Li, Wan Zhang (co-first author), Hui Zhang, Wenya Tian, Lian Wu, Shuwen Wang, Jun Zhang, Chenghai Sun, Yuhui Sun, Zixin Deng, Xudong Qu*, Jiahai Zhou*.
Structural basis of a broadly selective acyltransferase from the polyketide synthase of splenocin.
Angewandte Chemie International Edition 2018, 57, 5823-5827.
Xianyi Mei, Xiaoli Yan (co-first author), Hui Zhang, Mingjia Yu, Guangqing Shen, Linjun Zhou, Zixin Deng, Chun Lei, Xudong Qu*.
Expanding the bioactive chemical space of anthrabenzoxocinones through engineering the highly promiscuous biosynthetic modification steps.
ACS Chemical Biology 2018, 13, 200-206.
Jinmei Zhu, Hongqun Tan, Lu Yang, Zheng Dai, Lu Zhu, Hongmin Ma, Zixin Deng, Zhenghua Tian, Xudong Qu*.
Enantioselective synthesis of 1-aryl-substituted tetrahydroisoquinolines employing imine reductase.
ACS Catalysis 2017, 7, 7003-7007.
Chengcheng Chang, Rong Huang (co-first author), Yan Yan, Hongmin Ma, Zheng Dai, Benying Zhang, Wen Liu, Zixin Deng, Xudong Qu*.
Uncovering the formation and selection of benzylmalonyl-CoA from the biosynthesis of splenocin and enterocin reveals a versatile way to introduce amino acids into Polyketide carbon scaffolds.
Journal of the American Chemical Society 2015, 137, 4183-4190.