Enzymatic synthesis of organoselenium compounds via C‒Se bond formation mediated by sulfur carrier proteins

Zhang, Xingwang; Cheng, Fangyuan; Guo, Jiawei; Zheng, Shanmin; Wang, Xuan; Li, Shengying

doi:10.1038/s44160-023-00477-2

“…Very recently chemoenzymatic seleno compound synthesis by using selenium carrier proteins has been also established. [31] Finally, our findings are also relevant from an agricultural perspective. 6TG is a critical virulence factor of the notorious plant pathogen E. amylovora, which causes devastating losses in pome tree plantations, and due to antibiotic resistance it is very difficult to control fire blight with currently available means.…”

Section: Discussionmentioning

confidence: 68%

An Enzymatic Prodrug‐like Route to Thio and Selenoamides

Ishida,

Litomska,

Dunbar

et al. 2024

Angewandte Chemie

0

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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 analogue. 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.

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An Enzymatic Prodrug‐like Route to Thio and Selenoamides

Ishida,

Litomska,

Dunbar

et al. 2024

Angew Chem Int Ed

0

View full text Add to dashboard Cite

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 analogue. 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.

show abstract