Genetic interception and structural characterization of thiopeptide cyclization precursors from Bacillus cereus.
The pyridine core of the thiocillins has long been postulated to arise from a late-stage tail-to-tail condensation of two dehydroalanines. Genetic disruption of tclM, a proposed "Diels-Alderase", allowed isolation of acyclic precursors to this pyridine ring. The isolated products possess the full cohort of post-translational modifications that are normally displayed by the thiocillins, including dehydrobutyrines, thiazoles, C-terminal decarboxylation, and the two previously unconfirmed dehydroalanines. Additionally, leader peptides have undergone extensive N-terminal degradation and the remaining leader peptide residues have been N-succinylated. These results identify TclM and its homologues in other thiazolyl peptide producing strains as the enzymes responsible for the trans-annular heteroannulation at core of this class of molecules.
Bowers
Albert A
AA
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Walsh
Christopher T
CT
Acker
Michael G
MG
D001409:Bacillus cereus / Q000737:chemistry* / Q000378:metabolism; D003500:Cyclization; D005823:Genetics; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry* / Q000378:metabolism
D010455:Peptides; D011725:Pyridines; D013844:Thiazoles; C023666:pyridine