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. 2012 Nov 14;134(45):18518-21.
doi: 10.1021/ja308318p. Epub 2012 Nov 2.

Cylindrocyclophane biosynthesis involves functionalization of an unactivated carbon center

Hitomi Nakamura  1 , Hilary A Hamer, Gopal Sirasani, Emily P Balskus
Affiliations

Cylindrocyclophane biosynthesis involves functionalization of an unactivated carbon center

Hitomi Nakamura et al. J Am Chem Soc. .

Abstract

The cylindrocyclophanes are a family of natural products that share a remarkable paracyclophane carbon scaffold. Using genome sequencing and bioinformatic analyses, we have discovered a biosynthetic gene cluster involved in the assembly of cylindrocyclophane F. Through a combination of in vitro enzyme characterization and feeding studies, we confirm the connection between this gene cluster and cylindrocyclophane production, elucidate the chemical events involved in initiating and terminating an unusual type I polyketide synthase assembly line, and discover that macrocycle assembly involves functionalization of an unactivated carbon center.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
The cylindrocyclophane family of natural products and previous biosynthetic studies. (A) Structures of cylindrocyclophanes isolated from C. licheniforme strains ATCC 29204 and 29412. (B) Feeding studies performed by Bobzin and Moore revealed the polyketide origin of the cylindrocyclophanes. (C) Biosynthetic hypothesis put forth by Bobzin and Moore (reference 4).
Figure 2
Figure 2
Discovery of the cyl gene cluster and proposed biosynthesis of the cylindrocyclophanes. (A) HMG-CoA synthase homologs involved in β-methyl group installation on polyketide scaffolds. (B) The putative cyl gene cluster. Each arrow represents the direction of transcription of an open reading frame (ORF). See SI for complete cluster annotation. (C) Biosynthetic hypothesis for the assembly of the cylindrocyclophanes.
Figure 3
Figure 3
In vitro characterization of CylA and CylB. (A) HPLC assay showing the loading of decanoic acid onto holo-CylB by CylA. (B) LC-MS competition assay reveals selectivity for C10 fatty acid activation by CylA and CylB.
Figure 4
Figure 4
In vitro characterization of CylI. HPLC time course for formation of resorcinol 8 (230 nm).
Figure 5
Figure 5
Incorporation of labeled decanoic acid into cylindrocyclophane F by C. licheniforme.
See this image and copyright information in PMC

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