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. 2015 Jul 6;16(10):1443-7.
doi: 10.1002/cbic.201500177. Epub 2015 May 15.

Salinipyrone and Pacificanone Are Biosynthetic By-products of the Rosamicin Polyketide Synthase

Takayoshi Awakawa  1   2 , Max Crüsemann  1 , Jason Munguia  3 , Nadine Ziemert  1 , Victor Nizet  3   4 , William Fenical  1 , Bradley S Moore  5   6
Affiliations

Salinipyrone and Pacificanone Are Biosynthetic By-products of the Rosamicin Polyketide Synthase

Takayoshi Awakawa et al. Chembiochem. .

Abstract

Salinipyrones and pacificanones are structurally related polyketides from Salinispora pacifica CNS-237 that are proposed to arise from the same modular polyketide synthase (PKS) assembly line. Genome sequencing revealed a large macrolide PKS gene cluster that codes for the biosynthesis of rosamicin A and a series of new macrolide antibiotics. Mutagenesis experiments unexpectedly correlated salinipyrone and pacificanone biosynthesis to the rosamicin octamodule Spr PKS. Remarkably, this bifurcated polyketide pathway illuminates a series of enzymatic domain- and module-skipping reactions that give rise to natural polyketide product diversity. Our findings enlarge the growing knowledge of polyketide biochemistry and illuminate potential challenges in PKS bioengineering.

Keywords: Salinispora; biosynthesis; macrolide antibiotics; polyketide synthases.

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Figures

Figure 1
Figure 1
(A) HPLC chromatograms of the metabolites from i) CNS-237 wild-type, ii) spr10Y1290F, and iii) Δspr cultured in A1FeBC medium. The traces represent chromatograms acquired by detection at 254 nm. (* indicates the compound whose MS and UV spectrum are identical to 1.) Though 9 is eluted at the same RT as the compound marked with an asterisk, the peak of 9 is detected at 280 nm only in the Y1290F strain (Figure S2). (B) Chemical structures of 4–9.
Scheme 1
Scheme 1
The chemical structures of salinipyrone A (1), pacificanone A (2), and rosamicin A (3)
Scheme 2
Scheme 2
Proposed biosynthesis of 1–9. (A) Spr PKS organization and deduced assembly of 1–9. The arrows depict the sequential synthesis of intermediates leading to the mature products 3 and 5–8. The dotted arrows represent module skipping movements leading to 1 and 4. The bold arrow shows the assembly of 9, while the bold dotted arrow leading to 2 involves the skipping of the final module. In both cases, the KR domain in module 7 is inactive. The formation of 1 (B) and 2 (C) involve reactions on premature ACP-bound intermediates.
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