Journal
CHEMBIOCHEM
Volume 12, Issue 17, Pages 2677-2685Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201100494
Keywords
antibiotics; biosynthesis; coumermycin A1; isotopic labeling; Streptomyces
Funding
- German Federal Ministry of Education and Research (BMBF GenBioCom)
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Coumermycin A1 is an aminocoumarin antibiotic produced by Streptomyces rishiriensis. It contains three pyrrole rings, that is, two terminal 5-methyl-pyrrole-2-carboxyl moieties and a central 3-methylpyrrole-2,4-dicarboxylic acid moiety. The biosynthesis of the terminal pyrrole moieties has been elucidated previously. However, the biosynthetic precursors of the central pyrrole moiety have remained unknown, and none of the genes or enzymes involved in its formation has been identified. We now show that five genes, contained in a contiguous 4.7 kb region within the coumermycin biosynthetic gene cluster, are required for the biosynthesis of this central pyrrole moiety. Each of these genes was deleted individually, resulting in a strong reduction or an abolishment of coumermycin production. External feeding of the central pyrrole moiety restored coumermycin production. One of these genes shows similarity to L-threonine kinase genes. Feeding of [U-13C,15N]L-threonine and 13C NMR analysis of the resulting compound unequivocally proved that threonine was incorporated intact into the central pyrrole (19?% enrichment) to provide the heterocyclic nitrogen as well as four of the seven carbons of this moiety. Therefore, this pyrrole is formed via a new, hitherto unknown biosynthetic pathway. A hypothesis for the reaction sequence leading to the central pyrrole moiety of coumermycin A1 is presented.
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