The condensing activities of the Mycobacterium tuberculosis type II fatty acid synthase are differentially regulated by phosphorylation.
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 beta-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.
Molle
Virginie
V
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.
Brown
Alistair K
AK
Besra
Gurdyal S
GS
Cozzone
Alain J
AJ
Kremer
Laurent
L
D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000378:metabolism; D000123:Acetyltransferases / Q000378:metabolism* / Q000502:physiology; D001426:Bacterial Proteins / Q000378:metabolism; D054889:Fatty Acid Synthase, Type II; D009097:Multienzyme Complexes / Q000378:metabolism* / Q000502:physiology; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000378:metabolism; D009171:Mycolic Acids / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D013379:Substrate Specificity
D001426:Bacterial Proteins; D009097:Multienzyme Complexes; D009171:Mycolic Acids; D000123:Acetyltransferases; C444656:KasB protein, Mycobacterium tuberculosis; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; D017346:Protein Serine-Threonine Kinases; D054889:Fatty Acid Synthase, Type II