Gao Bo, Yang Bo, Feng Xudong, Li Chun
Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Ministry of Industry and Information Technology, Institute of Biochemical Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, China.
SynBio Research Platform, Collaborative Innovation Center of Chemical Science and Engineering, Key Laboratory of Systems Bioengineering, Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin, China.
Nat Prod Rep. 2022 Jan 26;39(1):139-162. doi: 10.1039/d1np00017a.
Covering: 2015 to 2020Nitrogen heterocyclic natural products (NHNPs) are primary or secondary metabolites containing nitrogen heterocyclic (N-heterocyclic) skeletons. Due to the existence of the N-heterocyclic structure, NHNPs exhibit various bioactivities such as anticancer and antibacterial, which makes them widely used in medicines, pesticides, and food additives. However, the low content of these NHNPs in native organisms severely restricts their commercial application. Although a variety of NHNPs have been produced through extraction or chemical synthesis strategies, these methods suffer from several problems. The development of biotechnology provides new options for the production of NHNPs. This review introduces the recent progress of two strategies for the biosynthesis of NHNPs: enzymatic biosynthesis and microbial cell factory. In the enzymatic biosynthesis part, the recent progress in the mining of enzymes that synthesize N-heterocyclic skeletons (, pyrrole, piperidine, diketopiperazine, and isoquinoline), the engineering of tailoring enzymes, and enzyme cascades constructed to synthesize NHNPs are discussed. In the microbial cell factory part, with tropane alkaloids (TAs) and tetrahydroisoquinoline (THIQ) alkaloids as the representative compounds, the strategies of unraveling unknown natural biosynthesis pathways of NHNPs in plants are summarized, and various metabolic engineering strategies to enhance their production in microbes are introduced. Ultimately, future perspectives for accelerating the biosynthesis of NHNPs are discussed.
2015年至2020年
氮杂环天然产物（NHNPs）是含有氮杂环骨架的初级或次级代谢产物。由于氮杂环结构的存在，NHNPs表现出多种生物活性，如抗癌和抗菌活性，这使得它们在医药、农药和食品添加剂中得到广泛应用。然而，这些NHNPs在天然生物体中的含量较低，严重限制了它们的商业应用。尽管已经通过提取或化学合成策略生产了多种NHNPs，但这些方法存在一些问题。生物技术的发展为NHNPs的生产提供了新的选择。本文综述了NHNPs生物合成的两种策略的最新进展：酶促生物合成和微生物细胞工厂。在酶促生物合成部分，讨论了合成氮杂环骨架（如吡咯、哌啶、二酮哌嗪和异喹啉）的酶的挖掘、修饰酶的工程改造以及构建用于合成NHNPs的酶级联反应的最新进展。在微生物细胞工厂部分，以托烷生物碱（TAs）和四氢异喹啉（THIQ）生物碱为代表性化合物，总结了揭示植物中NHNPs未知天然生物合成途径的策略，并介绍了提高它们在微生物中产量的各种代谢工程策略。最后，讨论了加速NHNPs生物合成的未来前景。
