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BIOLOGICAL SCIENCES / BIOCHEMISTRY
Cloning and characterization of the biosynthetic gene cluster for kutznerides

Danica Galoni Fujimori, Sinia Hrvatin, Christopher S. Neumann, Matthias Strieker^,, Mohamed A. Marahiel, and Christopher T. Walsh^,

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; and Department of Chemistry/Biochemistry, Philipps University, 35032 Marburg, Germany

Contributed by Christopher T. Walsh, August 30, 2007 (received for review August 2, 2007)

Kutznerides, actinomycete-derived cyclic depsipetides, consist of six nonproteinogenic residues, including a highly oxygenated tricyclic hexahydropyrroloindole, a chlorinated piperazic acid, 2-(1-methylcyclopropyl)-glycine, a β-branched-hydroxy acid, and 3-hydroxy glutamic acid, for which biosynthetic logic has not been elucidated. Herein we describe the biosynthetic gene cluster for the kutzneride family, identified by degenerate primer PCR for halogenating enzymes postulated to be involved in biosyntheses of these unusual monomers. The 56-kb gene cluster encodes a series of six nonribosomal peptide synthetase (NRPS) modules distributed over three proteins and a variety of tailoring enzymes, including both mononuclear nonheme iron and two flavin-dependent halogenases, and an array of oxygen transfer catalysts. The sequence and organization of NRPS genes support incorporation of the unusual monomer units into the densely functionalized scaffold of kutznerides. Our work provides insight into the formation of this intriguing class of compounds and provides a foundation for elucidating the timing and mechanisms of their biosynthesis.

chlorination | halogenases | nonribosomal peptide biosynthesis

The authors declare no conflict of interest.

Data deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. EU074211).

This article contains supporting information online at www.pnas.org/cgi/content/full/0708242104/DC1.

To whom correspondence should be addressed. E-mail: christopher_walsh{at}hms.harvard.edu

© 2007 by The National Academy of Sciences of the USA

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