| | |  | | | | Record from Web of Science® | | | | | | |
| Structural basis for macrolactonization by the pikromycin thioesterase |
|
|
| Author(s): Akey DL (Akey, David L.), Kittendorf JD (Kittendorf, Jeffrey D.), Giraldes JW (Giraldes, John W.), Fecik RA (Fecik, Robert A.), Sherman DH (Sherman, David H.), Smith JL (Smith, Janet L.) |
| Source: NATURE CHEMICAL BIOLOGY Volume: 2 Issue: 10 Pages: 537-542 Published: OCT 2006 |
| Times Cited: 32 References: 21 |
| Abstract: 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 agents(1). 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Smith, JL (reprint author), Univ Michigan, Inst Life Sci, 210 Washtenaw Ave, Ann Arbor, MI 48109 USA |
Addresses:
1. Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA
2. Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA
3. Univ Michigan, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA
4. Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA
5. Univ Michigan, Dept Biol Chem, Ann Arbor, MI 48109 USA
6. Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA |
| Publisher: NATURE PUBLISHING GROUP, 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA |
| Subject Category: Biochemistry & Molecular Biology |
| IDS Number: 095IX |
| ISSN: 1552-4450 |
| DOI: 10.1038/nchembio824 |
|
| | | | | | | | | Record from Web of Science® | | | | | | | | | |