AI Article Synopsis
- Bacterial trans-acyltransferase polyketide synthases (trans-AT PKSs) are large enzymes that create various bioactive compounds, including anticancer agents like oximidine.
- Researchers identified the gene cluster for oximidine in the bacterium Pseudomonas baetica and discovered four new variants, highlighting a simpler intermediate with strong anticancer properties.
- The study also detailed the oximidine biosynthesis process, revealing a unique mechanism for forming O-methyloxime involving a specific monooxygenase and methyltransferase, expanding knowledge on trans-AT PKSs and their potential for creating new drug variants.
Article Abstract
Bacterial trans-acyltransferase polyketide synthases (trans-AT PKSs) are modular megaenzymes that employ unusual catalytic domains to assemble diverse bioactive natural products. One such PKS is responsible for the biosynthesis of the oximidine anticancer agents, oxime-substituted benzolactone enamides that inhibit vacuolar H -ATPases. Here, we describe the identification of the oximidine gene cluster in Pseudomonas baetica and the characterization of four novel oximidine variants, including a structurally simpler intermediate that retains potent anticancer activity. Using a combination of in vivo, in vitro and computational approaches, we experimentally elucidate the oximidine biosynthetic pathway and reveal an unprecedented mechanism for O-methyloxime formation. We show that this process involves a specialized monooxygenase and methyltransferase domain and provide insight into their activity, mechanism and specificity. Our findings expand the catalytic capabilities of trans-AT PKSs and identify potential strategies for the production of novel oximidine analogues.
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| http://dx.doi.org/10.1002/anie.202304476 | DOI Listing |
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