Microbial Cell Factory for Efficiently Synthesizing Plant Natural Products via Optimizing the Location and Adaptation of Pathway on Genome Scale

Plant natural products (PNPs) possess important pharmacological activities and are widely used in cosmetics, health care products, and as food additives. Currently, most PNPs are mainly extracted from cultivated plants, and the yield is limited by the long growth cycle, climate change and complex processing steps, which makes the process unsustainable. However, the complex structure of PNPs significantly reduces the efficiency of chemical synthesis. With the development of metabolic engineering and synthetic biology, heterologous biosynthesis of PNPs in microbial cell factories offers an attractive alternative. Based on the in-depth mining and analysis of genome and transcriptome data, the biosynthetic pathways of a number of natural products have been successfully elucidated, which lays the crucial foundation for heterologous production. However, there are several problems in the microbial synthesis of PNPs, including toxicity of intermediates, low enzyme activity, multiple auxotrophic dependence, and uncontrollable metabolic network. Although various metabolic engineering strategies have been developed to solve these problems, optimizing the location and adaptation of pathways on the whole-genome scale is an important strategy in microorganisms. From this perspective, this review introduces the application of CRISPR/Cas9 in editing PNPs biosynthesis pathways in model microorganisms, the influences of pathway location, and the approaches for optimizing the adaptation between metabolic pathways and chassis hosts for facilitating PNPs biosynthesis.