Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 22, Pages 8511-8516Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0511129103
Keywords
fatty acid synthase; lipid metabolism; mycolic acids; polyketide
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Mycobacterium tuberculosis contains > 20 enzymes that require activation by transfer of the 4'-phosphopantetheine moiety of CoA onto a conserved serine residue, a posttranslational modification catalyzed by 4'-phosphopantetheinyl transferases (PPTases). The modified proteins are involved in key metabolic processes such as cell envelope biogenesis and the production of virulence factors. We show that two PPTases conserved in all Mycobacterium spp. and in related genera activate two different subsets of proteins and are not functionally redundant. One enzyme, AcpS, activates the two fatty acid synthase systems of mycobacteria, whereas the other PPTase, PptT, acts on type-l polyketide synthases and non-ribosomal peptide synthases, both of which are involved in the biosynthesis of virulence factors. We demonstrate that both PPTases are essential for Mycobacterium smegmatis viability and that PptT is required for the survival of Mycobacterium bovis bacillus Calmette-Guerin. These enzymes are thus central to the biology of mycobacterial and for mycobacterial pathogenesis and represent promising targets for new antituberculosis drugs.
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