Biosynthesis of Waspergillamide A Involves Unclustered Genes and a depsi-Tetrapeptide Diketopiperazine-Forming NRPS
Xian-Liang Zeng1, Wencong Yang2, Yi-Fan Du1
1State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, China.
Abstract:
Comparative genomics identified a nonribosomal peptide synthetase gene cluster (wpa), spanning two genomic scaffolds, responsible for waspergillamide A (1) in Aspergillus sp. CMB-W031. Pathway reconstitution revealed the cytochrome P450 WpaD as a gatekeeper: its presence directs biosynthesis toward the depsi-tetrapeptide diketopiperazine 2, which spontaneously dehydrates to 1 under weak acid condition, whereas its absence yields linear tetrapeptide 4. Pathway characterization further enabled structural revision of 1 and confirmed the conservation of p-nitrobenzoic acid biosynthesis in fungi.
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