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J. Biol. Chem., Vol. 281, Issue 40, 30094-30103, October 6, 2006

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The Condensing Activities of the Mycobacterium tuberculosis Type II Fatty Acid Synthase Are Differentially Regulated by Phosphorylation^*

Virginie Molle, Alistair K. Brown, Gurdyal S. Besra¹, Alain J. Cozzone, and Laurent Kremer^¶2

From the Institut de Biologie et Chimie des Protéines (IBCP UMR 5086), CNRS, Université Lyon1, IFR128 BioSciences, Lyon-Gerland, 7 Passage du Vercors, 69367 Lyon Cedex 07, France, the School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom, and the ^¶Laboratoire de Dynamique Moléculaire des Interactions Membranaires, CNRS UMR 5539, Université de Montpellier II, case 107, Place Eugène Bataillon, 34095 Montpellier Cedex 05, France

Phosphorylation of proteins by Ser/Thr protein kinases (STPKs) has recently become of major physiological importance because of its possible involvement in virulence of bacterial pathogens. Although Mycobacterium tuberculosis has eleven STPKs, the nature and function of the substrates of these enzymes remain largely unknown. In this work, we have identified for the first time STPK substrates in M. tuberculosis forming part of the type II fatty acid synthase (FAS-II) system involved in mycolic acid biosynthesis: the malonyl-CoA::AcpM transacylase mtFabD, and the -ketoacyl AcpM synthases KasA and KasB. All three enzymes were phosphorylated in vitro by different kinases, suggesting a complex network of interactions between STPKs and these substrates. In addition, both KasA and KasB were efficiently phosphorylated in M. bovis BCG each at different sites and could be dephosphorylated by the M. tuberculosis Ser/Thr phosphatase PstP. Enzymatic studies revealed that, whereas phosphorylation decreases the activity of KasA in the elongation process of long chain fatty acids synthesis, this modification enhances that of KasB. Such a differential effect of phosphorylation may represent an unusual mechanism of FAS-II system regulation, allowing pathogenic mycobacteria to produce full-length mycolates, which are required for adaptation and intracellular survival in macrophages.

Received for publication, February 22, 2006 , and in revised form, July 5, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ A Lister-Jenner Research Fellow supported by a grant from the Medical Research Council (MRC).

² Supported by a grant from the CNRS (ATIP Microbiologie Fondamentale). To whom correspondence should be addressed. Tel.: 33-4-67-14-33-81; Fax: 33-4-67-14-42-86; E-mail: laurent.kremer{at}univ-montp2.fr.

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