Abstract
Non-ribosomal peptide synthetases are mega-enzyme assembly lines that synthesize many clinically useful compounds. As a gatekeeper, they have an adenylation (A)-domain that controls substrate specificity and plays an important role in product structural diversity. This review summarizes the natural distribution, catalytic mechanism, substrate prediction methods, and in vitro biochemical analysis of the A-domain. Taking genome mining of polyamino acid synthetases as an example, we introduce research on mining non-ribosomal peptides based on A-domains. We discuss how non-ribosomal peptide synthetases can be engineered based on the A-domain to obtain novel non-ribosomal peptides. This work provides guidance for screening non-ribosomal peptide-producing strains, offers a method to discover and identify A-domain functions, and will accelerate the engineering and genome mining of non-ribosomal peptide synthetases.
Key points
• Introducing adenylation domain structure, substrate prediction, and biochemical analysis methods
• Advances in mining homo polyamino acids based on adenylation domain analysis
• Creating new non-ribosomal peptides by engineering adenylation domains
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Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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This work was funded by the National Nature Science Foundation of China (22208027), the Natural Science Foundation of the Jiangsu (BK20201050), the Natural Science Research Project of Jiangsu Higher Education Institutions (20KJB530019), the China Postdoctoral Science Foundation (2021M6691557), the Agricultural Science and Technology Innovation Project of Suzhou(SNG2022059), the Plan of Gusu Leading Talents of Innovation and Entrepreneurship Science and Technology (ZXL2022003), the Science and Technology Development Project of Suzhou (SNG2021018), and the Science and Technology Plan of Changshu (CS202109).
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DL conceived and wrote the manuscript. ZH and LY designed and generated the figures. LT, YB, ML, and HX gave critical insights on the subjects, reviewed, and improved the manuscript. All authors read and approved the final manuscript.
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Xu, D., Zhang, Z., Yao, L. et al. Advances in the adenylation domain: discovery of diverse non-ribosomal peptides. Appl Microbiol Biotechnol 107, 4187–4197 (2023). https://doi.org/10.1007/s00253-023-12585-2
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DOI: https://doi.org/10.1007/s00253-023-12585-2