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. 2017 Feb 24;80(2):363-370.
doi: 10.1021/acs.jnatprod.6b00808. Epub 2017 Jan 20.

Identification of Cyclic Depsipeptides and Their Dedicated Synthetase from Hapsidospora irregularis

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Identification of Cyclic Depsipeptides and Their Dedicated Synthetase from Hapsidospora irregularis

Shuwei Zhang et al. J Nat Prod. .

Abstract

Seven cyclic depsipeptides were isolated from Hapsidospora irregularis and structurally characterized as the calcium channel blocker leualacin and six new analogues based on the NMR and HRESIMS data. These new compounds were named leualacins B-G. The absolute configurations of the amino acids and 2-hydroxyisocaproic acids were determined by recording the optical rotation values. Biological studies showed that calcium influx elicited by leualacin F in primary human lobar bronchial epithelial cells involves the TRPA1 channel. Through genome sequencing and targeted gene disruption, a noniterative nonribosomal peptide synthetase was found to be involved in the biosynthesis of leualacin. A comparison of the structures of leualacin and its analogues indicated that the A2 and A4 domains of the leualacin synthetase are substrate specific, while A1, A3, and A5 can accept alternative precursors to yield new molecules.

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Conflict of interest statement

Notes

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Selected 1H-1H COSY and HMBC correlations for 2–7.
Figure 2
Figure 2
Proposed biosynthesis of 1 by a non-iterative NRPS.
Figure 3
Figure 3
Disruption of lacs in H. irregularis. (A) Strategy for targeted disruption of lacs. (B) Verification of the correct mutant by PCR. (C) HPLC analysis of the products of the wild type and mutant on the oatmeal agar plates at 210 nm. (i) wild type; (ii) mutant; (iii) standard of 1; (iv) standard of 2.

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