Biosynthesis of Tasikamides via Pathway Coupling and Diazonium-Mediated Hydrazone Formation

Naturally occurring hydrazones are rare despite the ubiquitous usage of synthetic hydrazones in the preparation of organic compounds and functional materials. In this study, we discovered a family of novel microbial metabolites (tasikamides) that share a unique cyclic pentapeptide scaffold. Surprisi...

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Veröffentlicht in:Journal of the American Chemical Society 2022-02, Vol.144 (4), p.1622-1633
Hauptverfasser: Ma, Guang-Lei, Candra, Hartono, Pang, Li Mei, Xiong, Juan, Ding, Yichen, Tran, Hoa Thi, Low, Zhen Jie, Ye, Hong, Liu, Min, Zheng, Jie, Fang, Mingliang, Cao, Bin, Liang, Zhao-Xun
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Sprache:eng
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Zusammenfassung:Naturally occurring hydrazones are rare despite the ubiquitous usage of synthetic hydrazones in the preparation of organic compounds and functional materials. In this study, we discovered a family of novel microbial metabolites (tasikamides) that share a unique cyclic pentapeptide scaffold. Surprisingly, tasikamides A–C (1–3) contain a hydrazone group (CNN) that joins the cyclic peptide scaffold to an alkyl 5-hydroxylanthranilate (AHA) moiety. We discovered that the biosynthesis of 1–3 requires two discrete gene clusters, with one encoding a nonribosomal peptide synthetase (NRPS) pathway for assembling the cyclic peptide scaffold and another encoding the AHA-synthesizing pathway. The AHA gene cluster encodes three ancillary enzymes that catalyze the diazotization of AHA to yield an aryl diazonium species (diazo-AHA). The electrophilic diazo-AHA undergoes nonenzymatic Japp–Klingemann coupling with a β-keto aldehyde-containing cyclic peptide precursor to furnish the hydrazone group and yield 1–3. The studies together unraveled a novel mechanism whereby specialized metabolites are formed by the coupling of two biosynthetic pathways via an unprecedented in vivo Japp–Klingemann reaction. The findings raise the prospect of exploiting the arylamine-diazotizing enzymes (AAD) for the in vivo synthesis of aryl compounds and modification of biological macromolecules.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.1c10369