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

Autor:	Ma GL; School of Biological Sciences, Nanyang Technological University, 637551 Singapore., Candra H; School of Biological Sciences, Nanyang Technological University, 637551 Singapore., Pang LM; School of Biological Sciences, Nanyang Technological University, 637551 Singapore., Xiong J; School of Pharmacy, Fudan University, Shanghai 201203, P. R. China., Ding Y; Temasek Life Sciences Laboratory Limited, Research Link, National University of Singapore, 117604 Singapore., Tran HT; School of Biological Sciences, Nanyang Technological University, 637551 Singapore., Low ZJ; School of Biological Sciences, Nanyang Technological University, 637551 Singapore., Ye H; School of Biological Sciences, Nanyang Technological University, 637551 Singapore., Liu M; School of Civil and Environmental Engineering, Nanyang Technological University, 639798 Singapore., Zheng J; School of Civil and Environmental Engineering, Nanyang Technological University, 639798 Singapore., Fang M; School of Civil and Environmental Engineering, Nanyang Technological University, 639798 Singapore., Cao B; School of Civil and Environmental Engineering, Nanyang Technological University, 639798 Singapore.; Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, 637551 Singapore., Liang ZX; School of Biological Sciences, Nanyang Technological University, 637551 Singapore.
Jazyk:	angličtina
Zdroj:	Journal of the American Chemical Society [J Am Chem Soc] 2022 Feb 02; Vol. 144 (4), pp. 1622-1633. Date of Electronic Publication: 2022 Jan 21.
DOI:	10.1021/jacs.1c10369
Abstrakt:	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.
Databáze:	MEDLINE
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