The nonredundant roles of two 4′-phosphopantetheinyl transferases in vital processes of Mycobacteria

doi:10.1073/pnas.0511129103

The nonredundant roles of two 4′-phosphopantetheinyl transferases in vital processes of Mycobacteria

^†Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique and Université P. Sabatier (Unité Mixte de Recherche 5089), 205 Route de Narbonne, 31077 Toulouse Cedex, France; and
^§Laboratoire de Biotechnologie des Microorganismes d’Intérêt Industriel, Institut de Génétique et Microbiologie, Centre National de la Recherche Scientifique and Université Paris Sud (Unité Mixte de Recherche 8621), Bat 409, 91405 Orsay Cedex, France

Edited by E. Peter Greenberg, University of Washington School of Medicine, Seattle, WA, and approved April 14, 2006 (received for review December 23, 2005)

Abstract

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-I polyketide synthases and nonribosomal 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–Guérin. These enzymes are thus central to the biology of mycobacteria and for mycobacterial pathogenesis and represent promising targets for new antituberculosis drugs.

Footnotes

^‡To whom correspondence should be addressed. E-mail: christian.chalut{at}ipbs.fr
Author contributions: C.C. and C.G. designed research; C.C., L.B., and C.d.S.-D. performed research; C.C., C.H., and C.G. analyzed data; and C.C. and C.G. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Abbreviations:

DIM,

phthiocerol dimycocerosates;

PGL-tb,

phenolic glycolipid;

Pks,

polyketide synthase;

Fas,

fatty acid synthase;

P-pant,

4′-phosphopantetheine;

NRPS,

nonribosomal peptide synthases;

PPTase,

4′-phosphopantetheinyl transferase;

ACP,

acyl carrier protein;

ATc,

anhydrotetracycline;

Km,

kanamycin.