Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 7, Pages 2069-2074Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0507924103
Keywords
biosynthesis; mycobactin; siderophore; acyl-transferase; dehydrogenase
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Funding
- Wellcome Trust Funding Source: Medline
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Mycobactins are a family of membrane-associated siderophores required for Mycobacterium tuberculosis to adapt to its intracellular habitat. These lipophilic siderophores have been recently shown to directly acquire intracellular iron through lipid trafficking. Despite tremendous progress in understanding the assembly-line enzymology of the siderophore biosynthesis, the genes as well as the mechanistic and biochemical principles involved in producing membrane-associated siderophores have not been investigated. Here, we report a biosynthetic locus that incorporates variety of aliphatic chains on the mycobactin skeleton. Cell-free reconstitution studies demonstrate that these acyl chains are directly transferred from a carrier protein on to the e-amino group of lysine residue by an unidentified Rv1347c gene product. The unsaturation in the lipidic chain is produced by a novel acyl-acyl carrier protein dehydrogenase, which, in contrast to the conventional acyl-CoA dehydrogenases, is involved in the biosynthetic pathway. MbtG protein then performs the final N16-hydroxylation step. Genome-wide analysis revealed homologues of N-acyltransferase and MbtG in other pathogenic bacteria. Because iron plays a key role in the development of infectious diseases, the biosynthetic pathway described here represents an attractive target for developing new antibacterial agents.
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