2hfj

Pikromycin thioesterase with covalent pentaketide affinity label

spinqualitylabelsall models 2hfj, resolution 1.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2hfj is a 2 chain structure with sequence from Streptomyces venezuelae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.95Å Ligands: DMS, MG, SO4, YML Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PIKA4_STRVZ Involved in the biosynthesis of 12- and 14-membered ring macrolactone antibiotics such as methymycin and neomethymycin, and pikromycin and narbomycin, respectively. Component of the pikromycin PKS which catalyzes the biosynthesis of both precursors 10-deoxymethynolide (12-membered ring macrolactone) and narbonolide (14-membered ring macrolactone). Chain elongation through PikAI, PikAII and PikAIII followed by thioesterase catalyzed termination results in the production of 10-deoxymethynolide, while continued elongation through PikAIV, followed by thioesterase (TE) catalyzed cyclization results in the biosynthesis of the narbonolide. The thioesterase can use a series of diketide-N-acetylcysteamine (SNAC) thioesters, but has a strong preference for the 2-methyl-3-ketopentanoyl-SNAC over the stereoisomers of 2-methyl-3-hydroxyacyl-SNAC (PubMed:12379101, PubMed:12733905). Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed 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. Structural basis for macrolactonization by the pikromycin thioesterase.,Akey DL, Kittendorf JD, Giraldes JW, Fecik RA, Sherman DH, Smith JL Nat Chem Biol. 2006 Oct;2(10):537-42. Epub 2006 Sep 10. PMID:16969372 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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