生物合成
大肠杆菌
生物化学
大肠杆菌蛋白质类
生物
基因
计算生物学
微生物学
化学
作者
Wenna Li,Zhao Zhou,Xianglai Li,Lin Ma,Qingyuan Guan,Guojun Zheng,Hao Liang,Yajun Yan,Xiaolin Shen,Wentao Jia,Xinxiao Sun,Qipeng Yuan
标识
DOI:10.1038/s41467-022-33255-3
摘要
Dencichine is a plant-derived nature product that has found various pharmacological applications. Currently, its natural biosynthetic pathway is still elusive, posing challenge to its heterologous biosynthesis. In this work, we design artificial pathways through retro-biosynthesis approaches and achieve de novo production of dencichine. First, biosynthesis of the two direct precursors L-2, 3-diaminopropionate and oxalyl-CoA is achieved by screening and integrating microbial enzymes. Second, the solubility of dencichine synthase, which is the last and only plant-derived pathway enzyme, is significantly improved by introducing 28 synonymous rare codons into the codon-optimized gene to slow down its translation rate. Last, the metabolic network is systematically engineered to direct the carbon flux to dencichine production, and the final titer reaches 1.29 g L-1 with a yield of 0.28 g g-1 glycerol. This work lays the foundation for sustainable production of dencichine and represents an example of how synthetic biology can be harnessed to generate unnatural pathways to produce a desired molecule.
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