Biosynthesis of HSAF, a Tetramic Acid-Containing Macrolactam from Lysobacter enzymogenes

HSAF was isolated from Lysobacter enzymogenes, a bacterium used in the biological control of fungal diseases of plants. Structurally, it is a tetramic acid-containing macrolactam fused to a tricyclic system. HSAF exhibits a novel mode of action by disrupting sphingolipids important to the polarized...

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Published in:Journal of the American Chemical Society 2011-02, Vol.133 (4), p.643-645
Main Authors: Lou, Lili, Qian, Guoliang, Xie, Yunxuan, Hang, Jiliang, Chen, Haotong, Zaleta-Rivera, Kathia, Li, Yaoyao, Shen, Yuemao, Dussault, Patrick H, Liu, Fengquan, Du, Liangcheng
Format: Article
Language:English
Subjects:
Antifungal Agents - chemistry
Antifungal Agents - metabolism
Lactams, Macrocyclic - chemistry
Lactams, Macrocyclic - metabolism
Lysobacter - enzymology
Lysobacter - genetics
Lysobacter - metabolism
Multigene Family
Peptide Synthases - genetics
Peptide Synthases - metabolism
Polyketide Synthases - genetics
Polyketide Synthases - metabolism
Pyrrolidinones - chemistry
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Summary:HSAF was isolated from Lysobacter enzymogenes, a bacterium used in the biological control of fungal diseases of plants. Structurally, it is a tetramic acid-containing macrolactam fused to a tricyclic system. HSAF exhibits a novel mode of action by disrupting sphingolipids important to the polarized growth of filamentous fungi. Here we describe the HSAF biosynthetic gene cluster, which contains only a single-module polyketide synthase/nonribosomal peptide synthetase (PKS/NRPS), although the biosynthesis of HSAF apparently requires two separate polyketide chains that are linked together by one amino acid (ornithine) via two amide bonds. Flanking the PKS/NRPS are six genes that encoding a cascade of four tightly clustered redox enzymes on one side and a sterol desaturase/fatty acid hydroxylase and a ferredoxin reductase on the other side. The genetic data demonstrate that the four redox genes, in addition to the PKS/NRPS gene and the sterol desaturase/fatty acid hydroxylase gene, are required for HSAF production. The biochemical data show that the adenylation domain of the NRPS specifically activates l-ornithine and that the four-domain NRPS is able to catalyze the formation of a tetramic acid-containing product from acyl-S-ACP and ornithinyl-S-NRPS. These results reveal a previously unrecognized biosynthetic mechanism for hybrid PK/NRP in prokaryotic organisms.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja105732c