Letter abstract
Nature Chemical Biology 2, 537 - 542 (2006)
Published online: 10 September 2006 | doi:10.1038/nchembio824
Structural basis for macrolactonization by the pikromycin thioesterase
David L Akey1,7, Jeffrey D Kittendorf1,2,7, John W Giraldes3, Robert A Fecik3, David H Sherman1,2,4,5 & Janet L Smith1,6
Polyketides are a class of biologically active microbial and plant-derived metabolites that possess a high degree of structural and functional diversity and include many human therapeutics, among them anti-infective and anti-cancer drugs, growth promoters and anti-parasitic agents1. The macrolide antibiotics, characterized by a glycoside-linked macrolactone, constitute an important class of polyketides, including erythromycin and the natural ketolide anti-infective agent pikromycin. Here we describe new mechanistic details of macrolactone ring formation catalyzed by the pikromycin polyketide synthase thioesterase domain from Streptomyces venezuelae. A pentaketide phosphonate mimic of the final pikromycin linear chain-elongation intermediate was synthesized and shown to be an active site affinity label. The crystal structures of the affinity-labeled enzyme and of a 12-membered-ring macrolactone product complex suggest a mechanism for cyclization in which a hydrophilic barrier in the enzyme and structural restraints of the substrate induce a curled conformation to direct macrolactone ring formation.
- Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109-2216, USA
- Department of Medicinal Chemistry, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109-2216, USA.
- Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street S.E., 8-101 Weaver–Densford Hall, Minneapolis, Minnesota 55455-0353, USA.
- Department of Microbiology & Immunology, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109-2216, USA.
- Department of Chemistry, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109-2216, USA.
- Department of Biological Chemistry, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109-2216, USA.
- These authors contributed equally to this work.
Correspondence to: Janet L Smith1,6 e-mail: JanetSmith@umich.edu
Correspondence to: Robert A Fecik3 e-mail: fecik001@umn.edu
Correspondence to: David H Sherman1,2,4,5 e-mail: davidhs@umich.edu
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