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Modular Oxime Formation by a trans-AT Polyketide Synthase
Hannah A Minas1, Romain M M François1,2, Franziska Hemmerling1
1Institute of Microbiology, Eidgenössische Technische Hochschule (ETH) Zürich, Vladimir-Prelog-Weg 4, 8093, Zürich, Switzerland.
Angewandte Chemie (International Ed. in English)
|May 22, 2023
Summary
Modular trans-acyltransferase polyketide synthases (trans-AT PKSs) create diverse natural products. This study reveals an unusual oxygenase module that installs methylated oximes on-line, expanding the toolbox for trans-AT PKS engineering.
Area of Science:
- Biochemistry
- Molecular Biology
- Natural Product Biosynthesis
Background:
- Modular trans-acyltransferase polyketide synthases (trans-AT PKSs) are crucial for synthesizing complex polyketide natural products.
- trans-AT PKSs offer greater chemical diversity compared to cis-AT PKSs.
- The lobatamide A PKS is a notable example, featuring a unique methylated oxime modification.
Purpose of the Study:
- To biochemically characterize the mechanism of oxime formation in the lobatamide A PKS.
- To elucidate the structural basis of the oxygenase's catalytic activity and protein interactions.
- To expand the engineering capabilities of trans-AT PKS for novel polyketide synthesis.
Main Methods:
- Biochemical assays to demonstrate on-line functionality of the oxygenase module.
- X-ray crystallography to determine the oxygenase crystal structure.
- Site-directed mutagenesis to identify key residues and interactions.
Main Results:
- The unusual oxygenase-containing bimodule was confirmed to install methylated oximes on-line.
- A catalytic model for the oxygenase was proposed based on structural analysis and mutagenesis.
- Key protein-protein interactions essential for the observed chemistry were identified.
Conclusions:
- Oxime-forming machinery has been added to the biomolecular engineering toolbox for trans-AT PKS.
- This advancement enables the introduction of masked aldehyde functionalities into diverse polyketides.
- The findings pave the way for creating novel polyketide natural products with tailored chemical properties.
![Solid-phase Synthesis of [4.4] Spirocyclic Oximes](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F58508.jpg&w=3840&q=50)
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