title: Iron acquisition in plague: modular logic in enzymatic biogenesis of yersiniabactin by Yersinia pestis.
abstract: BACKGROUND
  Virulence in the pathogenic bacterium Yersinia pestis, causative agent of bubonic plague, has been correlated with the biosynthesis and transport of an iron-chelating siderophore, yersiniabactin, which is induced under iron-starvation conditions. Initial DNA sequencing suggested that this system is highly conserved among the pathogenic Yersinia. Yersiniabactin contains a phenolic group and three five-membered thiazole heterocycles that serve as iron ligands.
  
  
  RESULTS
  The entire Y. pestis yersiniabactin region has been sequenced. Sequence analysis of yersiniabactin biosynthetic regions (irp2-ybtE and ybtS) reveals a strategy for siderophore production using a mixed polyketide synthase/nonribosomal peptide synthetase complex formed between HMWP1 and HMWP2 (encoded by irp1 and irp2). The complex contains 16 domains, five of them variants of phosphopantetheine-modified peptidyl carrier protein or acyl carrier protein domains. HMWP1 and HMWP2 also contain methyltransferase and heterocyclization domains. Mutating ybtS revealed that this gene encodes a protein essential for yersiniabactin synthesis.
  
  
  CONCLUSIONS
  The HMWP1 and HMWP2 domain organization suggests that the yersiniabactin siderophore is assembled in a modular fashion, in which a series of covalent intermediates are passed from the amino terminus of HMWP2 to the carboxyl terminus of HMWP1. Biosynthetic labeling studies indicate that the three yersiniabactin methyl moieties are donated by S-adenosylmethionine and that the linker between the thiazoline and thiazolidine rings is derived from malonyl-CoA. The salicylate moiety is probably synthesized using the aromatic amino-acid biosynthetic pathway, the final step of which converts chorismate to salicylate. YbtS might be necessary for converting chorismate to salicylate.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Gehring
authors.forename: E
authors.initials: E
authors.lastname: DeMoll
authors.forename: J D
authors.initials: JD
authors.lastname: Fetherston
authors.forename: I
authors.initials: I
authors.lastname: Mori
authors.forename: G F
authors.initials: GF
authors.lastname: Mayhew
authors.forename: F R
authors.initials: FR
authors.lastname: Blattner
authors.forename: C T
authors.initials: CT
authors.lastname: Walsh
authors.forename: R D
authors.initials: RD
authors.lastname: Perry
mesh_terms: D000595:Amino Acid Sequence; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D001483:Base Sequence; D017931:DNA Primers; D007501:Iron / Q000378:metabolism*; D033862:Iron-Binding Proteins; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism*; D033902:Periplasmic Binding Proteins; D010636:Phenols; D010930:Plague / Q000378:metabolism*; D020156:Salicylic Acid / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D017262:Siderophores / Q000096:biosynthesis*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013844:Thiazoles; D014774:Virulence; D015010:Yersinia pestis / Q000378:metabolism / Q000472:pathogenicity
chemical_list: D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D017931:DNA Primers; D033862:Iron-Binding Proteins; D009097:Multienzyme Complexes; D033902:Periplasmic Binding Proteins; D010636:Phenols; D017262:Siderophores; D013844:Thiazoles; C104398:yersiniabactin; D007501:Iron; D020156:Salicylic Acid