Recently, the microbial intelligent design and synthesis innovation team of the Institute of biotechnology, Chinese Academy of Agricultural Sciences, in cooperation with foreign scientific research institutions, comprehensively summarized the main progress, bottlenecks and development direction of the engineering transformation of fungal non ribosomal peptide biosynthesis pathway in the past decade. Relevant review articles are published in natural product reports.
The secondary metabolites of non ribosomal peptides synthesized by fungi are important sources of medical and agricultural drugs, such as penicillin, cephalosporin, echinocandin and pf1022a, which play an important role in antibacterial and insecticidal activities. This paper systematically summarizes four methods of engineering transformation of the current fungal non ribosomal peptide biosynthesis pathway:protobacterial activation and heterologous expression, precursor oriented biosynthesis and mutation synthesis, combinatorial biosynthesis and enzyme engineering, in vitro biosynthesis and chemical enzyme synthesis. Then, the engineering transformation of oligocyclic peptide, cyclic peptide and cyclic peptide, polyketo non ribosomal peptide hybrid molecule and non ribosomal peptide synthase involved in the biosynthesis pathway were summarized. At present, the most in-depth research on the bioengineering modification of fungal non ribosomal peptide is the insecticidal oligocyclic peptide synthesized by biocontrol fungi, which shows the great potential of synthesizing new skeletal active products by modifying non ribosomal peptide synthase, and also provides a paradigm for the research of other types of fungal non ribosomal peptide synthase. However, due to the technical bottleneck of heterologous expression of most fungal giant non ribosomal peptide synthase (more than hundreds or even thousands of daltons), the transformation of non ribosomal peptide synthase with more than three modules is rarely reported. This paper further analyzes the gap between the theory and the existing methods, especially with the engineering transformation of prokaryotic non ribosomal peptide synthesis pathway, discusses the limitations of the current field and the priority development direction, and provides constructive suggestions for the upgrading of future engineering strategies.
The research was supported by the National Natural Science Foundation of China and the science and technology innovation project of the Chinese Academy of Agricultural Sciences.