title: Characterization of the cereulide NRPS alpha-hydroxy acid specifying modules: activation of alpha-keto acids and chiral reduction on the assembly line.
abstract: Several nonribosomal peptide natural products are composites of alpha-hydroxy acid and alpha-amino acid monomers. Cereulide, the emetic toxin from the human pathogen Bacillus cereus, and valinomycin, from Streptomyces spp., are closely related macrocyclic K+ ionophores. The macrocyclic core of each natural product contains alternating peptide (six) and ester (six) bonds, and their cyclododecadepsipeptide structures consist of a tetradepsipeptide unit repeated three times. Here we overexpress the cereulide NRPS alpha-hydroxy acid specifying modules from CesA and CesB and demonstrate that each contains an alpha-keto acid activating adenylation domain and a chiral alpha-ketoacyl-S-carrier protein reductase (alpha-KR). The logic used by the cereulide NRPS is likely at work in the valinomycin NRPS and may be the general strategy used in bacterial NRPSs to form alpha-hydroxy acid containing natural products.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Magarvey
authors.forename: Monika
authors.initials: M
authors.lastname: Ehling-Schulz
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Walsh
mesh_terms: D047630:Depsipeptides / Q000737:chemistry* / Q000378:metabolism*; D007651:Keto Acids / Q000737:chemistry*; D015394:Molecular Structure; D010453:Peptide Synthases / Q000378:metabolism*; D014634:Valinomycin / Q000737:chemistry / Q000378:metabolism
chemical_list: D047630:Depsipeptides; D007651:Keto Acids; C089294:cereulide; D014634:Valinomycin; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase