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A new family of ATP-dependent oligomerization-macrocyclization biocatalysts

Nature Chemical Biology volume 3, pages 652–656 (2007)Cite this article

An Erratum to this article was published on 01 April 2009

This article has been updated

Abstract

Oligomerization and macrocyclization reactions are key steps in the biosynthesis of many bioactive natural products. Important macrocycles include the antibiotic daptomycin (1; ref. 1), the immunosuppressant FK-506 (2; ref. 2), the anthelmintic avermectin B1a (3; ref. 3) and the insecticide spinosyn A (4; ref. 4); important oligomeric macrocycles include the siderophores enterobactin (5; ref. 5) and desferrioxamine E (6; ref. 6). Biosynthetic oligomerization and macrocyclization reactions typically involve covalently tethered intermediates and are catalyzed by thioesterase domains of polyketide synthase and nonribosomal peptide synthetase multienzymes7. Here we report that the purified recombinant desferrioxamine siderophore synthetase DesD from Streptomyces coelicolor M145 catalyzes ATP-dependent trimerization-macrocyclization of a chemically synthesized 10-aminocarboxylic acid substrate via noncovalently bound intermediates. DesD is dissimilar to other known synthetase families but is similar to other enzymes known or proposed to be required for the biosynthesis of ω-aminocarboxylic acid–derived cyclodimeric siderophores8,9. This suggests that DesD is the first biochemically characterized member of a new family of oligomerizing and macrocyclizing synthetases.

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Figure 1: Structures of related oligomeric and oligomeric-macrocyclic hydroxamate-based siderophores known or hypothesized to be biosynthesized by the new family of synthetases.
Figure 2: Organization of the gene cluster directing desferrioxamine biosynthesis and ferrioxamine uptake in S. coelicolor, and proposed pathway for desferrioxamine biosynthesis.
Figure 3: Identification of HSC as an intermediate in desferrioxamine biosynthesis and characterization of the catalytic properties of the desferrioxamine synthetase DesD.
Figure 4

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Change history

  • 18 March 2009

    In the version of this article initially published, an extra methyl group was inadvertently added to the structure of desferrioxamine G1 and related compounds. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank L. Song for assistance with the LC-MS and MS/MS analyses and T.D.H. Bugg for helpful discussions. This research was funded by grants to G.L.C. from the Biotechnology and Biological Sciences Research Council SPoRT initiative (Grant ref. BBS/B/14450) and exploiting genomics initiative (Grant Ref. EGH16081).

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Author notes

  1. Francisco Barona-Gomez

    Present address: Present address: Departamento de Ingeniería Celular y Biocatálisis, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Apartado Postal 510-3, Cuernavaca, C.P. 62250, México.,

Authors and Affiliations

  1. Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK

    Nadia Kadi, Daniel Oves-Costales, Francisco Barona-Gomez & Gregory L Challis

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Contributions

N.K. designed experiments, performed experiments, interpreted data and wrote the paper; D.O.-C. designed experiments, performed experiments, interpreted data and wrote the paper; F.B.-G. designed experiments, performed experiments and interpreted data; G.L.C. designed experiments, interpreted data and wrote the paper.

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Correspondence to Gregory L Challis.

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Supplementary Figures 1–7, Supplementary Table 1 and Supplementary Methods (PDF 165 kb)

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Kadi, N., Oves-Costales, D., Barona-Gomez, F. et al. A new family of ATP-dependent oligomerization-macrocyclization biocatalysts. Nat Chem Biol 3, 652–656 (2007). https://doi.org/10.1038/nchembio.2007.23

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