An Enzymatic Prodrug‐like Route to Thio and Selenoamides
Abstract: 6‐Thioguanine (6TG) is a clinically used antitumor agent that was rationally designed as a DNA‐targeting antimetabolite, but it also occurs naturally. 6TG is a critical virulence factor produced by Erwinia amylovorans, a notorious plant pathogen that causes fire blight of pome fruit trees. The biosynthesis of the rare thioamide metabolite involves an adenylating enzyme (YcfA) and a sulfur‐mobilizing enzyme (YcfC), but the mechanism of sulfur transfer and putative intermediates have remained elusive. Through dissection and in vitro reconstitution of the thionation process using diverse substrates, we uncover an intermediate, prodrug‐like thio‐conjugate and elucidate the precise enzyme functions. YcfA not only adenylates GMP but also transfers the mercapto group of l‐cysteine to the activated carbonyl. A designated C−S lyase (YcfC) then cleaves the resulting S‐adduct to yield the thioamide. This pathway is distinct from canonical tRNA sulfur modifications and known enzymatic peptide thionations. By exploring a wide range of substrate surrogates, we exploited the tolerance of the enzyme pair to produce even a seleno analog. This study provides valuable insight into a previously unexplored area of bacterial thioamide formation and lays the groundwork for synthetic biology approaches to produce thioamide antimetabolites.
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Bibliographic citation
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An Enzymatic Prodrug‐like Route to Thio and Selenoamides ; day:27 ; month:06 ; year:2024 ; extent:9
Angewandte Chemie ; (27.06.2024) (gesamt 9)
- Creator
- DOI
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10.1002/ange.202404243
- URN
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urn:nbn:de:101:1-2406281412185.247379355746
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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14.08.2025, 11:00 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Ishida, Keishi
- Litomska, Agnieszka
- Dunbar, Kyle L.
- Hertweck, Christian
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Novel Biocatalysts from Specialized Metabolism
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Loss of Single‐Domain Function in a Modular Assembly Line Alters the Size and Shape of a Complex Polyketide
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An Enzymatic Prodrug‐like Route to Thio and Selenoamides
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Funktionalisierte Vinyloxirane durch reduktive Allylierung von Estern : stereoselektive Synthesen von Lamoxiren und Sphingoidbasen
A Photochemical Macrocyclization Route to Asymmetric Strained (3.2) Paracyclophanes
Photosensitizers Enable the Formation of Biphenyls with UV‐LEDs and Sunlight
Novel Biocatalysts from Specialized Metabolism
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Loss of Single‐Domain Function in a Modular Assembly Line Alters the Size and Shape of a Complex Polyketide
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Bacterial Isothiocyanate Biosynthesis by Rhodanese‐Catalyzed Sulfur Transfer onto Isonitriles
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