Evolution-guided engineering of trans-acyltransferase polyketide synthases
Bacterial multimodular polyketide synthases (PKSs) are giant enzymes that generate a wide range of therapeutically important but synthetically challenging natural products. Diversification of polyketide structures can be achieved by engineering these enzymes. However, notwithstanding successes made with textbook cis-acyltransferase (cis-AT) PKSs, tailoring such large assembly lines remains challenging. Unlike textbook PKSs, trans-AT PKSs feature an extraordinary diversity of PKS modules and commonly evolve to form hybrid PKSs. In this study, we analyzed amino acid coevolution to identify a common module site that yields functional PKSs. We used this site to insert and delete diverse PKS parts and create 22 engineered trans-AT PKSs from various pathways and in two bacterial producers. The high success rates of our engineering approach highlight the broader applicability to generate complex designer polyketides.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:383 |
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| Enthalten in: |
Science (New York, N.Y.) - 383(2024), 6689 vom: 22. März, Seite 1312-1317 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mabesoone, Mathijs F J [VerfasserIn] |
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| Links: |
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| Themen: |
79956-01-7 |
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| Anmerkungen: |
Date Completed 25.03.2024 Date Revised 26.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1126/science.adj7621 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Bacterial multimodular polyketide synthases (PKSs) are giant enzymes that generate a wide range of therapeutically important but synthetically challenging natural products. Diversification of polyketide structures can be achieved by engineering these enzymes. However, notwithstanding successes made with textbook cis-acyltransferase (cis-AT) PKSs, tailoring such large assembly lines remains challenging. Unlike textbook PKSs, trans-AT PKSs feature an extraordinary diversity of PKS modules and commonly evolve to form hybrid PKSs. In this study, we analyzed amino acid coevolution to identify a common module site that yields functional PKSs. We used this site to insert and delete diverse PKS parts and create 22 engineered trans-AT PKSs from various pathways and in two bacterial producers. The high success rates of our engineering approach highlight the broader applicability to generate complex designer polyketides | ||
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| 700 | 1 | |a Minas, Hannah A |e verfasserin |4 aut | |
| 700 | 1 | |a Chepkirui, Clara |e verfasserin |4 aut | |
| 700 | 1 | |a Chawengrum, Pornsuda |e verfasserin |4 aut | |
| 700 | 1 | |a Reiter, Silke |e verfasserin |4 aut | |
| 700 | 1 | |a Meoded, Roy A |e verfasserin |4 aut | |
| 700 | 1 | |a Wolf, Sarah |e verfasserin |4 aut | |
| 700 | 1 | |a Genz, Ferdinand |e verfasserin |4 aut | |
| 700 | 1 | |a Magnus, Nancy |e verfasserin |4 aut | |
| 700 | 1 | |a Piechulla, Birgit |e verfasserin |4 aut | |
| 700 | 1 | |a Walker, Allison S |e verfasserin |4 aut | |
| 700 | 1 | |a Piel, Jörn |e verfasserin |4 aut | |
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