2hfj

From Proteopedia

Pikromycin thioesterase with covalent pentaketide affinity label

Overview

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.

About this Structure

2HFJ is a Single protein structure of sequence from Streptomyces venezuelae with , , and as ligands. Full crystallographic information is available from OCA.

Reference

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

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