A role for antibiotic biosynthesis monooxygenase domain proteins in fidelity control during aromatic polyketide biosynthesis
| Autor: | Barrie Wilkinson, Zhiwei Qin, Matthew I. Hutchings, Rebecca Devine |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Methicillin-Resistant Staphylococcus aureus Science General Physics and Astronomy Polyketide biosynthesis Secondary Metabolism 02 engineering and technology Antibiotic biosynthesis medicine.disease_cause General Biochemistry Genetics and Molecular Biology Article Mixed Function Oxygenases Metabolic engineering 03 medical and health sciences Polyketide Bacterial Proteins Protein Domains Bacterial genetics Gene cluster medicine lcsh:Science Secondary metabolism Mutation Multidisciplinary Chemistry General Chemistry Monooxygenase 021001 nanoscience & nanotechnology Streptomyces 3. Good health Anti-Bacterial Agents Biosynthetic Pathways 030104 developmental biology Biochemistry Metabolic Engineering Multigene Family Polyketides lcsh:Q Natural product synthesis 0210 nano-technology |
| Zdroj: | Nature Communications Nature Communications, Vol 10, Iss 1, Pp 1-10 (2019) |
| ISSN: | 2041-1723 |
| Popis: | The formicamycin biosynthetic gene cluster encodes two groups of type 2 polyketide antibiotics: the formicamycins and their biosynthetic precursors the fasamycins, both of which have activity against methicillin-resistant Staphylococcus aureus. Here, we report the formicapyridines which are encoded by the same gene cluster and are structurally and biosynthetically related to the fasamycins and formicamycins but comprise a rare pyridine moiety. These compounds are trace-level metabolites formed by derailment of the major biosynthetic pathway. Inspired by evolutionary logic we show that rational mutation of a single gene in the biosynthetic gene cluster encoding an antibiotic biosynthesis monooxygenase (ABM) superfamily protein leads to a significant increase both in total formicapyridine production and their enrichment relative to the fasamycins/formicamycins. Our observations broaden the polyketide biosynthetic landscape and identify a non-catalytic role for ABM superfamily proteins in type II polyketide synthase assemblages for maintaining biosynthetic pathway fidelity. Formicapyridines are similar to pentacyclic fasamycin and formicamycin aromatic polyketides but with a pyridine moiety. Here the authors rationally mutate the biosynthetic gene cluster to increase production and identify a non-catalytic role for the ABM superfamily of proteins. |
| Databáze: | OpenAIRE |
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