Dynamic thiolation–thioesterase structure of a non-ribosomal peptide synthetase

Dominique P. Frueh (), Haribabu Arthanari, Alexander Koglin, David A. Vosburg, Andrew E. Bennett, Christopher T. Walsh () and Gerhard Wagner ()
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Dominique P. Frueh: Harvard Medical School, Boston, Massachusetts 02115, USA
Haribabu Arthanari: Harvard Medical School, Boston, Massachusetts 02115, USA
Alexander Koglin: Harvard Medical School, Boston, Massachusetts 02115, USA
David A. Vosburg: Harvard Medical School, Boston, Massachusetts 02115, USA
Andrew E. Bennett: Harvard Medical School, Boston, Massachusetts 02115, USA
Christopher T. Walsh: Harvard Medical School, Boston, Massachusetts 02115, USA
Gerhard Wagner: Harvard Medical School, Boston, Massachusetts 02115, USA

Nature, 2008, vol. 454, issue 7206, 903-906

Abstract: Biosynthetic enzymes: thioesterase-driven production lines Non-ribosomal peptide synthetases (NRPS) and polyketide synthases (PKS) are found in bacteria, fungi, and plants, in the main, producing antibiotics. They are macromolecular machines that rely on the activity of thioesterases to produce biologically active small molecules. They are of particular interest as an assembly system that might be adapted for the production of novel bioactive compounds with possible therapeutic activity. Frueh et al. have solved the structure of a carrier protein — part of the EntF NRPS subunit of enterobactin synthetase — bound to a type I thioesterase. (Type I thioesterases catalyse the final 'release' step of the small molecule from the NRPS or PKS machinery.) The structure reveals that part of the thioesterase can flip open to reveal the carrier-protein binding site of the enzyme; this movement allows the tether of the carrier protein to access the active site. Koglin et al. determined the structure of conformational sub-states of a thioesterase II enzyme. Type II thioesterases are required to regenerate a functional 4'-phosphopantetheine cofactor when it gets mis-primed by reacting with acetyl- and short chain acyl-residues. Comparison with the structures of type I thioesterases reveals the basis for substrate selectivity and the different modes of interaction of the two types of thioesterases with thiolation domains.

Date: 2008
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DOI: 10.1038/nature07162

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