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 β-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. 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 β-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. Mycobacterium tuberculosis has a unique cell wall structure that accounts for the ability of the bacterium to grow in several contrasting environments and which is responsible for its low membrane permeability, contributing to its resistance to common chemotherapeutic agents (1Brennan P.J. Nikaido H. Annu. Rev. Biochem. 1995; 64: 29-63Crossref PubMed Scopus (1572) Google Scholar). The cell wall has been implicated as a direct modulator of interactions between mycobacteria and the environment (2Daffe M. Draper P. Adv. Microb. Physiol. 1998; 39: 131-203Crossref PubMed Google Scholar). This envelope, characterized by its high lipid content, comprises an inner membrane barrier composed of mycolic acids anchored to arabinogalactan, linked to peptidoglycan. Mycolic acids are a hallmark of the mycobacterial waxy coat: they represent key virulence factors required for intracellular survival (3Dubnau E. Chan J. Raynaud C. Mohan V.P. Laneelle M.A. Yu K. Quemard A. Smith I. Daffe M. Mol. Microbiol. 2000; 36: 630-637Crossref PubMed Scopus (257) Google Scholar, 4Gao L.Y. Laval F. Lawson E.H. Groger R.K. Woodruff A. Morisaki J.H. Cox J.S. Daffe M. Brown E.J. Mol. Microbiol. 2003; 49: 1547-1563Crossref PubMed Scopus (151) Google Scholar) and contribute to the physiopathology of tuberculosis. They consist of very long chains of α-branched β-hydroxy fatty acids (C60-C90), whose biosynthesis is controlled by two elongation systems, the eukaryotic-type fatty acid synthase (FAS-I) 3The abbreviations used are: FAS-I, eukaryotic-type fatty acid synthase; AcpM, mycobacterial acyl carrier protein; FAS-II, prokaryotic type II fatty acid synthase; FHA, forkhead-associated domain; STPK, Ser/Thr protein kinase; NTA, nitrilotriacetic acid; PVDF, polyvinylidene difluoride; IPTG, isopropyl-1-thio-β-d-galactopyranoside; GST, glutathione S-transferase. and the prokaryotic-like FAS-II (5Takayama K. Wang C. Besra G.S. Clin. Microbiol Rev. 2005; 18: 81-101Crossref PubMed Scopus (509) Google Scholar, 6Kremer L. Baulard A.R. Besra G.S. Hatfull G.F. a.W.R.J. Jr. Molecular Genetics of Mycobacteria. ASM Press, Washington, D. C.2000: 173-190Google Scholar). FAS-I consists of a single multifunctional polypeptide, catalyzing de novo synthesis of medium length acyl-CoA chains (C16-C26), whereas FAS-II comprises several distinct enzymes. It catalyzes similar types of reactions to FAS-I, but functions on acyl carrier protein (AcpM)-bound chains and is incapable of de novo synthesis. The initial substrates of FAS-II are β-ketoacyl-AcpM resulting from the condensation by mtFabH of the acyl-CoA products of FAS-I with malonyl-AcpM (7Choi K.H. Kremer L. Besra G.S. Rock C.O. J. Biol. Chem. 2000; 275: 28201-28207Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 8Brown A.K. Sridharan S. Kremer L. Lindenberg S. Dover L.G. Sacchettini J.C. Besra G.S. J. Biol. Chem. 2005; 280: 32539-32547Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). Following reduction by MabA, elimination of water by a yet unidentified dehydratase, and reduction by the enoyl-AcpM reductase InhA, the β-ketoacyl-AcpM synthases KasA and KasB catalyze further condensations with malonyl-AcpM in the FAS-II cycle (9Schaeffer M.L. Agnihotri G. Volker C. Kallender H. Brennan P.J. Lonsdale J.T. J. Biol. Chem. 2001; 276: 47029-47037Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 10Kremer L. Dover L.G. Carrere S. Nampoothiri K.M. Lesjean S. Brown A.K. Brennan P.J. Minnikin D.E. Locht C. Besra G.S. Biochem. J. 2002; 364: 423-430Crossref PubMed Scopus (108) Google Scholar). Although changes in the mycolic acid profile seem to be regulated by various environmental stimuli, such as those encountered within the infected macrophage, very little is known at a molecular basis about how pathogenic mycobacteria modulate mycolate composition in response to these changes. Whether regulation of FAS-II enzymes occurs at the transcriptional and/or the translational level is not known. Elucidation of mechanisms modulating mycolic acid biosynthesis would shed some light on the capacity of M. tuberculosis to adapt and survive within the infected host. Reversible protein phosphorylation is a key mechanism by which environmental signals are transmitted to cause changes in protein expression or activity in both eukaryotes and prokaryotes. Genes encoding functional serine/threonine protein kinases (STPKs) are ubiquitous in prokaryotic genomes, but little is known regarding their physiological substrates and their participation in bacterial signal transduction pathways (11Av-Gay Y. Everett M. Trends Microbiol. 2000; 8: 238-244Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar). Understanding prokaryotic kinase biology has been seriously hampered by the failure to identify relevant kinase substrates. Signaling through Ser/Thr phosphorylation has emerged as a critical regulatory mechanism in various bacteria, including pathogenic mycobacteria. The genome of M. tuberculosis contains eleven coding regions with significant similarity to eukaryotic STPKs (11Av-Gay Y. Everett M. Trends Microbiol. 2000; 8: 238-244Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar, 12Cole S.T. Brosch R. Parkhill J. C. D. K. S. F. K. D. Brown D. R. R. K. S. S. K. A. J. S. L. K. J. M.A. M.A. J. S. K. J. R. S. K. S. 1998; PubMed Scopus Google Scholar). of these products are to be membrane a to the and a kinase to the (11Av-Gay Y. Everett M. Trends Microbiol. 2000; 8: 238-244Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar). All mycobacterial Ser/Thr kinases to and several substrates have been to be phosphorylated by these enzymes P. L. M. K. J. J. Biochem. PubMed Scopus Google Scholar, Y. S. PubMed Google Scholar, C. Kremer L. P. 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Besra G.S. 2003; PubMed Scopus Google of in the in those to a in the the coding and could be and as to the intracellular regions of the different kinases were with their by and and used in this and are by or to sites are from those in the type are and are by or sites are The from those in the type are in a the were used to of medium with and were at with at a of and for an at with of the proteins with as Kremer L. C. Besra G.S. 2003; PubMed Scopus Google Scholar). and of mtFabD, and to and KasA and were L. Dover L.G. Carrere S. Nampoothiri K.M. Lesjean S. Brown A.K. Brennan P.J. Minnikin D.E. Locht C. Besra G.S. Biochem. J. 2002; 364: 423-430Crossref PubMed Scopus (108) Google Scholar, L. Nampoothiri K.M. Lesjean S. Dover L.G. S. J. Brennan P.J. Minnikin D.E. Locht C. Besra G.S. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). The by M. tuberculosis as a and the and This the which been with and with the to E. with were used to of medium with were at with at a of and at with of mtFabD, KasB as L. Nampoothiri K.M. Lesjean S. Dover L.G. S. J. Brennan P.J. Minnikin D.E. Locht C. Besra G.S. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). and of and as L. Nampoothiri K.M. Lesjean S. Dover L.G. S. J. Brennan P.J. Minnikin D.E. Locht C. Besra G.S. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, S. Kremer L. E. Draper P. G. Mol. Microbiol. PubMed Scopus Google Scholar). of the of acid of the protein products of the in vitro protein kinase reactions were as C. P. E. C. G. PubMed Scopus Google Scholar). and of the M. tuberculosis KasA and KasB in M. bovis were used to the M. tuberculosis or the and a and a The products were with direct the expression with M. Brennan P.J. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). 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S. J. Brennan P.J. Minnikin D.E. Locht C. Besra G.S. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). AcpM, the mycobacterial acyl carrier is by a between and L. Dover L.G. Carrere S. Nampoothiri K.M. Lesjean S. Brown A.K. Brennan P.J. Minnikin D.E. Locht C. Besra G.S. Biochem. J. 2002; 364: 423-430Crossref PubMed Scopus (108) Google Scholar). used to the eleven STPKs of M. tuberculosis to these FAS-II All eleven STPKs were as and from E. The various FAS-II were as and from E. 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Biol. 2005; PubMed Scopus Google as as the proteins and C. 2005; PubMed Scopus Google Scholar). studies have interactions between proteins and STPKs to the or different This that the kinases substrates that the in to mechanisms direct to STPKs, the of STPKs in M. tuberculosis. from these is that and with STPKs, suggesting that these enzymes may be regulated by to be this STPK occurs in which would for a very complex All FAS-II on to which acid were phosphorylated by we the acid of phosphorylated and The different proteins were with in by and to acid as in Kremer L. C. Besra G.S. 2003; PubMed Scopus Google Scholar). that three substrates are phosphorylated at with of have recently that phosphorylation of in vitro to phosphorylation in Kremer L. Besra G.S. K. S. A. PubMed Scopus Google whereas phosphorylated at a single A. R. A. P. P. P. S.T. C. J. Mol. 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Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). from a phosphorylated for of the with and for and three phosphorylation sites were phosphorylation of KasB and In Phosphorylation of KasA and KasB in M. bovis KasA and KasB phosphorylation occurs in we have a M. bovis BCG proteins were on a which were to a membrane and with which with KasB. the of or of KasA and to various phosphorylation that both KasA and KasB are very efficiently phosphorylated in and that is significant in in vitro with STPKs The basis for the in the phosphorylation in vitro and in is but that the intracellular environment a key in the phosphorylation of KasA and KasB. which are from in vitro may be required for of the to the some STPKs may first in to the allowing kinases to the enzymes in a this a to for phosphorylation of mycobacterial In addition, may be to how the phosphorylation these that M. bovis BCG an of phosphorylated to for further studies to the effect of phosphorylation on the activity of the enzymes. and of KasA and KasB in in M. bovis and in phosphorylated a at the of the KasA and the protein in M. bovis of M. bovis were and to the from the cell KasA to by on that of this KasA by would to phosphorylation of KasA in and to a or were at various time M. bovis BCG to or and KasA at each time and to the first to the of KasA in the by and were that KasA is phosphorylated in the of KasA phosphorylated at or two sites the and a of KasA This with in vitro in which the of KasA the phosphorylation of KasA of the is that the phosphorylation profile different the in mycobacteria and characterized by the of to the of This with an suggesting that phosphorylation be in M. bovis BCG I. C. Microbiol. 2003; PubMed Scopus Google Scholar). the of KasB in M. bovis that both enzymes are phosphorylated in mycobacteria to a significant in phosphorylation of KasA and KasB occurs on and/or were or It that KasA and KasB from their M. bovis BCG were phosphorylated on This is with the by the proteins were phosphorylated in vitro It that both enzymes are phosphorylated in on In the the with KasA or KasB proteins from E. that the phosphorylation of the enzymes is a of M. bovis BCG M. tuberculosis tuberculosis has encoding a Ser/Thr phosphatase S.T. Brosch R. Parkhill J. C. D. K. S. F. K. D. Brown D. R. R. K. S. S. K. A. J. S. L. K. J. M.A. M.A. J. S. K. J. R. S. K. S. 1998; PubMed Scopus Google Scholar, M. R. F. S.T. C. Mol. Microbiol. 2003; 49: PubMed Scopus Google Scholar). efficiently a of phosphorylated including and P. R. R. A. H. M. P. A.K. Y. Biochem. 2003; PubMed Scopus Google Scholar, M. R. F. S.T. C. Mol. Microbiol. 2003; 49: PubMed Scopus Google Scholar) as as M. tuberculosis STPK R. A. M. A. P. S.T. C. Biochem. 2005; PubMed Scopus Google Scholar). of STPKs sites for substrates Kremer L. C. Besra G.S. 2003; PubMed Scopus Google Scholar) and protein kinase activity M. R. F. S.T. C. Mol. Microbiol. 2003; 49: PubMed Scopus Google Scholar). we the on in as be the phosphorylation activity is regulated and on a phosphorylation the of the phosphatase as a The as a protein in E. and with phosphorylated KasA from M. bovis revealed a single the and to an suggesting that dephosphorylated KasA this is the first time that has been to a mycobacterial suggesting that its phosphatase activity not on kinases but on the kinase substrates. that phosphorylation of KasA is in the phosphatase may a key regulatory Phosphorylation KasA and KasB and KasB have been to be β-ketoacyl-AcpM synthases of the mycobacterial FAS-II system L. Baulard A.R. Besra G.S. Hatfull G.F. a.W.R.J. Jr. Molecular Genetics of Mycobacteria. ASM Press, Washington, D. C.2000: 173-190Google Scholar, 10Kremer L. Dover L.G. Carrere S. Nampoothiri K.M. Lesjean S. Brown A.K. Brennan P.J. Minnikin D.E. Locht C. Besra G.S. Biochem. J. 2002; 364: 423-430Crossref PubMed Scopus (108) Google Scholar). FAS-II is responsible for the of the fatty acid that is to the chain of mycolic is very little as to mycolic acid biosynthesis be regulated to the regulatory of the phosphorylation of FAS-II enzymes. to the effect of phosphorylation on and of KasA and KasB. The effect of phosphorylation on KasA activity the protein from E. or from M. bovis BCG as of or phosphorylated and by both and malonyl-AcpM and The for substrates and malonyl-AcpM were about and and not on that phosphorylation not of these substrates. the by on to a reduction in the of the condensation these for phosphorylated KasB and In to we that phosphorylation the condensation activity of KasB. Although the for phosphorylation the of malonyl-AcpM by to that phosphorylation KasA and KasB and that they be phosphorylated at different their a phosphorylation produce this differential on in vitro and has been that KasA is involved in the initial elongation of acid that are further by KasB L. Baulard A.R. Besra G.S. Hatfull G.F. a.W.R.J. Jr. Molecular Genetics of Mycobacteria. ASM Press, Washington, D. C.2000: 173-190Google Scholar, 2002; PubMed Scopus Google Scholar). This has recently been by in studies in both and of but not could be in Mycobacterium suggesting that, is A. Kremer L. Sacchettini J.C. J. 2005; PubMed Scopus Google Scholar). It that of KasA in M. to the of mycolic acid biosynthesis to cell A. Kremer L. Sacchettini J.C. J. 2005; PubMed Scopus Google Scholar). of Mycobacterium an within infected KasB not required for in a critical of KasB in intracellular survival L.Y. Laval F. Lawson E.H. Groger R.K. Woodruff A. Morisaki J.H. Cox J.S. Daffe M. Brown E.J. Mol. Microbiol. 2003; 49: 1547-1563Crossref PubMed Scopus (151) Google Scholar). the were by in the and this to the of the chain L.Y. Laval F. Lawson E.H. Groger R.K. Woodruff A. Morisaki J.H. Cox J.S. Daffe M. Brown E.J. Mol. Microbiol. 2003; 49: 1547-1563Crossref PubMed Scopus (151) Google Scholar). the importance for pathogenic mycobacteria to produce full-length for intracellular survival and that KasA and KasB are and are and to the would that differential regulation at a a transcriptional that phosphorylation is the modification that the activity of KasA and enhances that of KasB. The differential effect of phosphorylation of KasA and two similar enzymes the activity but with different substrates is This is the that both enzymes a similar phosphorylation profile in and are phosphorylated at the This may represent an unusual mechanism of regulation KasA may time to produce KasB activity may that mycobacteria produce the full-length required for virulence and intracellular the substrates of M. tuberculosis STPKs identified mtFabD, KasA and KasB are the to which a function has been that phosphorylation of these enzymes a in the of the FAS-II and the for studies to the regulation of mycolic acid The differential expression of the mycobacterial kinases in response to may the phosphorylation profile of these and as a modulate mycolic acid biosynthesis in to adaptation to environmental changes. In an R. L. Daffe M. D. Mol. Microbiol. PubMed Scopus Google Scholar) have an on the between the various FAS-II in which different FAS-II are In this the of two FAS-II involved in the elongation the by a and of from FAS-I an the chain of products would be the the and KasB that would synthesis. a in which phosphorylation or to the and is to how environmental including those encountered within the infected this regulation recently that synthesis and with KasA A. M. A. Kremer L. Hatfull G.F. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). of M. that is in a reduction in KasA and KasB with phosphorylated KasA or KasB the proteins to be It may be to that a regulatory in phosphorylation of these proteins by the of this is the of a of for tuberculosis by with these regulatory such as by of This is by the that of protein kinases have been for a of D. A. 2002; Full Text Full Text PDF PubMed Scopus Google and a of to of M. tuberculosis A. A. G. L. C. K. C. G. J. PubMed Scopus Google Scholar). This a for of FAS-II regulation, not in mycobacteria but in and in which a FAS-II D. for the of the L. G. Dover of M. J. and D. A. for their on the

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