Emulating evolutionary processes to morph aureothin-type modular polyketide synthases and associated oxygenases
| Autor: | Christian Hertweck, Yuki Sugimoto, Keishi Ishida, Holger Jenke-Kodama, Huiyun Peng |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Antifungal medicine.drug_class Science General Physics and Astronomy Structural diversity 02 engineering and technology Computational biology Biology medicine.disease_cause Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Polyketide Antibiotics Phylogenetics medicine Amino Acid Sequence lcsh:Science Antifungal agents Phylogeny AKA Spectinabilin Mutation Multidisciplinary Molecular Structure business.industry General Chemistry Modular design 021001 nanoscience & nanotechnology Streptomyces Anti-Bacterial Agents 030104 developmental biology Models Chemical Chromones Polyketides Oxygenases Natural product synthesis lcsh:Q Genetic Engineering 0210 nano-technology business Polyketide Synthases Metabolic engineering |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-14 (2019) Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-019-11896-1 |
| Popis: | Polyketides produced by modular type I polyketide synthases (PKSs) play eminent roles in the development of medicines. Yet, the production of structural analogs by genetic engineering poses a major challenge. We report an evolution-guided morphing of modular PKSs inspired by recombination processes that lead to structural diversity in nature. By deletion and insertion of PKS modules we interconvert the assembly lines for related antibiotic and antifungal agents, aureothin (aur) and neoaureothin (nor) (aka spectinabilin), in both directions. Mutational and functional analyses of the polyketide-tailoring cytochrome P450 monooxygenases, and PKS phylogenies give contradictory clues on potential evolutionary scenarios (generalist-to-specialist enzyme evolution vs. most parsimonious ancestor). The KS-AT linker proves to be well suited as fusion site for both excision and insertion of modules, which supports a model for alternative module boundaries in some PKS systems. This study teaches important lessons on the evolution of PKSs, which may guide future engineering approaches. The wealth of complex polyketides is an essential source for drug discovery. Here, the authors report an evolution-guided rational morphing of modular polyketide synthases (PKSs) for aurothin and neoaurothin biosynthesis, and reveal engineering site suitable for diversifying PKS systems. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|