2HFK

Pikromycin thioesterase in complex with product 10-deoxymethynolide

Summary for 2HFK

• Entry DOI: 10.2210/pdb2hfk/pdb
• Related: 1MNA 2HFJ
• Descriptor: Type I polyketide synthase PikAIV, SULFATE ION, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: alpha/beta hydrolase, thioesterase, hydrolase
• Biological source: Streptomyces venezuelae
• Total number of polymer chains: 2
• Total formula weight: 68761.44

Authors

Akey, D.L.,Kittendorf, J.D.,Giraldes, J.W.,Fecik, R.A.,Sherman, D.H.,Smith, J.L. (deposition date: 2006-06-24, release date: 2006-09-19, Last modification date: 2023-08-30)

Primary citation

Akey, D.L.,Kittendorf, J.D.,Giraldes, J.W.,Fecik, R.A.,Sherman, D.H.,Smith, J.L.
Structural Basis for Macrolactonization by the Pikromycin Thioesterase
NAT.CHEM.BIOL., 2:537-542, 2006

PubMed 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. 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.

PubMed: 16969372
DOI: 10.1038/nchembio824

Experimental method

X-RAY DIFFRACTION (1.79 Å)