p-Hydroxybenzoic Acid Synthesis in Mycobacterium tuberculosis

Glycosylated p-hydroxybenzoic acid methyl esters and structurally related phenolphthiocerol glycolipids are important virulence factors of Mycobacterium tuberculosis. Although both types of molecules are thought to be derived from p-hydroxybenzoic acid, the origin of this putative biosynthetic precursor in mycobacteria remained to be established. We describe the characterization of a transposon mutant of M. tuberculosis deficient in the production of all forms of p-hydroxybenzoic acid derivatives. The transposon was found to be inserted in Rv2949c, a gene located in the vicinity of the polyketide synthase gene pks15/1, involved in the elongation of p-hydroxybenzoate to phenolphthiocerol in phenolic glycolipid-producing strains. A recombinant form of the Rv2949c enzyme was produced in the fast-growing non-pathogenic Mycobacterium smegmatis and purified to near homogeneity. The recombinant enzyme catalyzed the removal of the pyruvyl moiety of chorismate to form p-hydroxybenzoate with an apparent Km value for chorismate of 19.7 μm and a kcat value of 0.102 s-1. Strong inhibition of the reaction by p-hydroxybenzoate but not by pyruvate was observed. These results establish Rv2949c as a chorismate pyruvate-lyase responsible for the direct conversion of chorismate to p-hydroxybenzoate and identify Rv2949c as the sole enzymatic source of p-hydroxybenzoic acid in M. tuberculosis. Glycosylated p-hydroxybenzoic acid methyl esters and structurally related phenolphthiocerol glycolipids are important virulence factors of Mycobacterium tuberculosis. Although both types of molecules are thought to be derived from p-hydroxybenzoic acid, the origin of this putative biosynthetic precursor in mycobacteria remained to be established. We describe the characterization of a transposon mutant of M. tuberculosis deficient in the production of all forms of p-hydroxybenzoic acid derivatives. The transposon was found to be inserted in Rv2949c, a gene located in the vicinity of the polyketide synthase gene pks15/1, involved in the elongation of p-hydroxybenzoate to phenolphthiocerol in phenolic glycolipid-producing strains. A recombinant form of the Rv2949c enzyme was produced in the fast-growing non-pathogenic Mycobacterium smegmatis and purified to near homogeneity. The recombinant enzyme catalyzed the removal of the pyruvyl moiety of chorismate to form p-hydroxybenzoate with an apparent Km value for chorismate of 19.7 μm and a kcat value of 0.102 s-1. Strong inhibition of the reaction by p-hydroxybenzoate but not by pyruvate was observed. These results establish Rv2949c as a chorismate pyruvate-lyase responsible for the direct conversion of chorismate to p-hydroxybenzoate and identify Rv2949c as the sole enzymatic source of p-hydroxybenzoic acid in M. tuberculosis. The chorismate pathway, present only in bacteria, fungi, and plants, provides a wealth of compounds with diverse biological functions, including aromatic amino acids, folate cofactors, menaquinones, ubiquinones, pigments, and iron-chelating siderophores. Mycobacterium tuberculosis, the etiological agent of tuberculosis in humans, is no exception to the rule, and chorismate in this species is the probable common precursor for the biosynthesis of a series of products (see Fig. 1) that are important both in the physiology and in the pathogenicity of the bacterium. In addition to folate and aromatic amino acids (phenylalanine, tyrosine, and tryptophan), M. tuberculosis produces salicylic acid-derived siderophores known as mycobactins (1De Voss J.J. Rutter K. Schroeder B.G. Barry C.E. II I. J. Bacteriol. 1999; 181: 4443-4451Crossref PubMed Google Scholar), isoprenoid quinones of the naphthalene series (menaquinones) (2Collins M.D. Jones D. Microbiol. Rev. 1981; 45: 316-354Crossref PubMed Google Scholar), and glycosylated p-hydroxybenzoic acid methyl esters (p-HBAD 4The abbreviations used are: p-HBADp-hydroxybenzoic acid methyl ester4-HBp-hydroxybenzoic acidPGLphenolic glycolipidsMALDI-TOFmatrix-assisted laser desorption ionization time-of-flightGCgas chromatographyGC/MSGC/mass spectrometry.s) (3Constant P. Pérez E. Malaga W. Lanéelle M.-A. Saurel O. Daffé M. Guilhot C. J. Biol. Chem. 2002; 277: 38148-38158Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar). A few strains of M. tuberculosis also produce species-specific phenolic glycolipids (PGL), complex lipids of the cell envelope that share with p-HBADs the same glycosylated aromatic nucleus. These lipids and their counterparts found in Mycobacterium leprae have been largely associated with pathogenicity (4Brennan P.J. Ratledge C. Wilkinson S.G. Microbial Lipids. 1. Academic Press Ltd., London1988: 203-298Google Scholar, 5Chan J. Fujiwara T. Brennan P.J. McNeil M. Turco S.J. Sibille J.-C. Snapper M. Aisen P. Bloom B.R. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 2453-2457Crossref PubMed Scopus (205) Google Scholar, 6Puzo G. Critic. Rev. Microbiol. 1990; 17: 305-327Crossref PubMed Scopus (47) Google Scholar, 7Ng V. Zanazzi G. Timpl R. Talts J.F. Salzer J.L. Brennan P.J. Rambukkana A. Cell. 2000; 103: 511-524Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar, 8Schlesinger L.S. Horwitz M.A. J. Exp. Med. 1991; 174: 1031-1038Crossref PubMed Scopus (67) Google Scholar, 9Reed M.B. Domenech P. Manca C. Su H. Barczak A.K. Kreiswirth B.N. Kaplan G. Barry C.E. II I. Nature. 2004; 431: 84-87Crossref PubMed Scopus (606) Google Scholar). Likewise, preliminary data indicate that p-HBADs, which are essentially recovered from the secretion products of the tubercle bacillus, modulate the secretion of pro-inflammatory cytokines by murine macrophages (10Griffin R. Stadthagen Gomez G. Young D. Coade S. Bottová I. Nigou J. Brando T. Puzo G. Gicquel B. Lowrie D. Jackson M. Tascon R.E. Keystone Symposium, British Columbia, April 2-7, 2005, Bill and Melinda Gates Foundation. Whistler, British Columbia, Canada2005Google Scholar) and are required for virulence in immunodeficient mice (11Hisert K.B. Kirksey M.A. Gomez J.E. Sousa A.O. Cox J.S. Jr Jacobs W. R. Nathan, C.F. McKinney J.D. Infect. Immun. 2004; 72: 5315-5321Crossref PubMed Scopus (44) Google Scholar). p-hydroxybenzoic acid methyl ester p-hydroxybenzoic acid phenolic glycolipids matrix-assisted laser desorption ionization time-of-flight gas chromatography GC/mass spectrometry. Because of the important roles played by PGL and p-HBADs in the pathogenesis of mycobacterial infections, their biosynthesis has stimulated some interest, and, during the last decade, several genes involved in the synthesis of the lipid core of PGL and in the methylation and glycosylation of PGL and p-HBADs have been described (3Constant P. Pérez E. Malaga W. Lanéelle M.-A. Saurel O. Daffé M. Guilhot C. J. Biol. Chem. 2002; 277: 38148-38158Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar, 12Azad A.K. Siraková T.D. Rogers L.M. Kolattukudy P.E. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4787-4792Crossref PubMed Scopus (86) Google Scholar, 13Azad A.K. Siraková T.D. Fernandes N.D. Kolattukudy P.E. J. Biol. Chem. 1997; 272: 16741-16745Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 14Fitzmaurice A.M. Kolattukudy P.E. J. Biol. Chem. 1998; 273: 8033-8039Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 15Camacho L.R. Ensergueix D. Pérez E. Gicquel B. Guilhot C. Mol. Microbiol. 1999; 34: 257-267Crossref PubMed Scopus (517) Google Scholar, 16Cox J.S. Chen B. McNeil M. Jacobs Jr., W.R. Nature. 1999; 402: 79-83Crossref PubMed Scopus (615) Google Scholar, 17Camacho L.R. Constant P. Raynaud C. Lanéelle M.-A. Triccas J.A. Gicquel B. Daffé M. Guilhot C. J. Biol. Chem. 2001; 276: 19845-19854Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar, 18Pérez E. Constant P. Lemassu A. Laval F. Daffé M. Guilhot C. J. Biol. Chem. 2004; 279: 42574-42583Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 19Pérez E. Constant P. Laval F. Lemassu A. Lanéelle M.-A. Daffé M. Guilhot C. J. Biol. Chem. 2004; 279: 42584-42592Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 20Onwueme K.C. Ferreras J.A. Buglino J. Lima C.D. Quadri L.E.N. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 4608-4613Crossref PubMed Scopus (79) Google Scholar, 21Trivedi O.A. Arora P. Sridharan V. Tickoo R. Mohanty D. Gokhale R.S. Nature. 2004; 428: 441-445Crossref PubMed Scopus (228) Google Scholar, 22Trivedi O.A. Arora P. Vats A. Ansari M.Z. Tickoo R. Sridharan V. Mohanty D. Gokhale R.S. Mol. Cell. 2005; 17: 631-643Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). Most of these genes are clustered on a 70-kilobase region of the chromosome. The synthesis of both p-HBADs and PGL is thought to proceed from p-hydroxybenzoic acid. Comparison of the chemical structures of these compounds suggested that, in the biosynthetic route of p-HBADs, p-hydroxybenzoic acid would be first methylated to p-hydroxybenzoic acid methyl ester before being glycosylated and further methylated. In the case of PGL, p-hydroxybenzoic acid would be elongated by the specialized polyketide synthase Pks15/1 to give p-hydroxyphenylalkanoates, which would be in turn converted to phenolphthiocerol derivatives in catalytic reactions involving the PpsA-E synthases (3Constant P. Pérez E. Malaga W. Lanéelle M.-A. Saurel O. Daffé M. Guilhot C. J. Biol. Chem. 2002; 277: 38148-38158Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar). The resulting molecules or their diesters, the phenolphthiocerol dimycocerosates, would be then glycosylated and methylated by the same enzymes as those involved in the production of p-HBADs to yield the final PGL molecules (18Pérez E. Constant P. Lemassu A. Laval F. Daffé M. Guilhot C. J. Biol. Chem. 2004; 279: 42574-42583Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 19Pérez E. Constant P. Laval F. Lemassu A. Lanéelle M.-A. Daffé M. Guilhot C. J. Biol. Chem. 2004; 279: 42584-42592Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar). The origin of p-hydroxybenzoic acid (4-HB) in mycobacteria remains, however, to be established. In Escherichia coli, 4-HB formation from chorismate is the first committed step in ubiquinone synthesis. The reaction consists of the removal of the pyruvyl moiety of chorismate and is catalyzed by the enzyme chorismate pyruvate-lyase (p-hydroxybenzoic acid synthase) encoded by the ubiC gene (23Siebert M. Bechthold A. Melzer M. May U. Berger U. Schröder G. Schröder J. Severin K. Heide L. FEBS Lett. 1992; 307: 347-350Crossref PubMed Scopus (62) Google Scholar, 24Nichols B.P. Green J.M. J. Bacteriol. 1992; 174: 5309-5316Crossref PubMed Google Scholar). The apparent lack of production of isoprenoid quinones of the benzene series (ubiquinones) in M. tuberculosis (2Collins M.D. Jones D. Microbiol. Rev. 1981; 45: 316-354Crossref PubMed Google Scholar) and the absence of proteins sharing significant sequence similarities with UbiC in the genome of this bacterium made it unclear whether 4-HB formation in mycobacteria proceeded through the same route as in E. coli. In the present study, we the and characterization of a transposon mutant of M. tuberculosis deficient in the production of all forms of 4-HB derivatives and that Rv2949c, the gene by the transposon a chorismate pyruvate-lyase responsible for the formation of 4-HB from and the of M. tuberculosis used in this study, and the mutant in with and in M.B. C. R. Acad. Sci. Scholar) or on with acid, E. the used for was in M. smegmatis R.E. S. T. Jacobs W.R. Mol. Microbiol. 1990; PubMed Scopus Google Scholar) was in with and or in with and and to final of and of the transposon in was by as described G. B. V. Gicquel B. Guilhot C. Microbiol. Lett. 1998; PubMed Google Scholar). The used for and The products on a of M. tuberculosis and of Rv2949c in M. with used to the M. tuberculosis Rv2949c of step by of and and a final step for The and and to the Rv2949c gene for direct the and of the J. M. K. Puzo G. Brennan P.J. Gicquel B. Jackson M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). The recombinant Rv2949c produced by the a the and M. smegmatis with and for by on and B. The production of recombinant Rv2949c in and was by with a as described J. M. K. Puzo G. Brennan P.J. Gicquel B. Jackson M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). and of the of p-hydroxybenzoate the M. tuberculosis strains and in as production was by chromatography of lipids from and and through to yield lipids then by of and of to of to yield a The was and then by of The was with and to yield the lipid lipids from with for by with acid methyl esters from lipids and from by with by methylation with for and with In some M. tuberculosis in with acid a precursor in all of and acid methyl esters on in the for p-HBADs, for of and for acid and acid methyl in and a in a acid used to lipids and all lipids and acids by of to was by A. and V. from and mycobactins in the of as described Voss J.J. Rutter K. Schroeder B.G. Su H. Barry C.E. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar) and by the p-HBADs purified from the of the by as the The products of and from the with was a with a laser in the an and an in of The by of a in the The of acid in was The then to 4-HB derivatives by the reaction on in in of and The was and then with in of by the addition of of and of The reaction was for The was and the derivatives in for gas chromatography and or in for spectrometry. and a series with an gas with a ionization The was from to on a in with a series II gas with a and of from E. and M. M. tuberculosis Rv2949c gene was by from the of and to and direct of the the of the The resulting was used to E. in and then to of the same was to a final of and was for an of the recombinant was by with and by a E. recombinant enzyme and in A by on of on and and the resulting was for The was and the the M. tuberculosis was a proteins by the with A and to the was then with A of and The recombinant Rv2949c was by in the with and that to be by a in an and used for further the M. smegmatis Rv2949c, was of with the in and by and the production of recombinant Rv2949c was by as described the of recombinant Rv2949c of and in of A before for in the form of with The and by of the for and the recombinant Rv2949c was purified from the of this a as described for the recombinant produced in E. coli. Rv2949c was in the with and These and as described pyruvate-lyase was a to that of M. Severin K. Heide L. PubMed Scopus (86) Google Scholar). The of pyruvate from which in the of the was by in a reaction that was not in was in a The was and in a final of chorismate μm of and μm of purified recombinant Rv2949c the of for to reaction and to In some and inhibition by and from the reaction and the reactions by of The p-hydroxybenzoate in the reaction was and by of reaction was to an with a was acid as the of a Rv2949c of M. tuberculosis from a of M. tuberculosis transposon in a region of the associated with the synthesis of PGL and structurally related glycosylated p-HBADs (10Griffin R. Stadthagen Gomez G. Young D. Coade S. Bottová I. Nigou J. Brando T. Puzo G. Gicquel B. Lowrie D. Jackson M. Tascon R.E. Keystone Symposium, British Columbia, April 2-7, 2005, Bill and Melinda Gates Foundation. Whistler, British Columbia, Canada2005Google Scholar). of these which an from the of the gene Rv2949c, was for further Rv2949c is located from the genes in the genome of M. tuberculosis and has in species of mycobacteria as M. M. and M. In in the of Rv2949c and with Rv2949c the amino acid the amino acid Rv2949c amino some sequence similarities with putative chorismate (p-hydroxybenzoic acid from on a with the of on a with the of and on a but no significant similarities with the chorismate pyruvate-lyase of E. coli, the of Rv2949c on the suggested a of this gene in the of p-HBADs and PGL, we to whether it in the synthesis of the aromatic of these important biological of the Rv2949c found the of and Although the the and forms of p-hydroxybenzoic acid methyl and was no for the production of of these glycosylated 4-HB derivatives in the or in of also of was by with an as being acid methyl a form of an The was purified and first by spectrometry. The a value is that for that a to an form of the of in the was and by spectrometry. The of the a and The to the a the to forms of a that or These data that the a with and in with the a to a on the of the purified by and of the derivatives of the and of and as the of a not The moiety of the was by as p-hydroxybenzoic acid methyl ester not We that a to the form of in which the consists of The the by with the of (3Constant P. Pérez E. Malaga W. Lanéelle M.-A. Saurel O. Daffé M. Guilhot C. J. Biol. Chem. 2002; 277: 38148-38158Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar). a is an in the biosynthetic to from or a of of and of a in the and then to in the an and an in of The used of acid in of with a of Rv2949c of the and on a the production of all in the including that of and that of to be in as with of the of Rv2949c in the only a of 4-HB be by in the lipid from the and strains not that this is synthesis. The of Rv2949c on PGL production not be in the of this as the M. tuberculosis is of these molecules (3Constant P. Pérez E. Malaga W. Lanéelle M.-A. Saurel O. Daffé M. Guilhot C. J. Biol. Chem. 2002; 277: 38148-38158Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar). of and lipids from and no or in the cell envelope or in the products of the strains their not Likewise, the same types and of and glycolipids and recovered from and not as chorismate pyruvate-lyase in the formation of 4-HB from and pyruvate-lyase for the formation of salicylic acid from we whether the of Rv2949c in on the production of salicylic acid-derived mycobactins was further by the that, to the genes involved in the formation of the moiety in siderophores have not been (1De Voss J.J. Rutter K. Schroeder B.G. Barry C.E. II I. J. Bacteriol. 1999; 181: 4443-4451Crossref PubMed Google Scholar, F. J. Rev. Microbiol. 2001; PubMed Scopus Google Scholar). this and in which was to the and the forms of and by was found the strains that Rv2949c is not required for the same as in and in not In with the the of the in was by that of Rv2949c some on the was not with to the known and of 4-HB esters Chem. 2002; PubMed Scopus Google Scholar). these results that Rv2949c the enzyme responsible for the production of the aromatic of all p-HBADs and that it is the sole enzymatic source of 4-HB in M. tuberculosis. of of Rv2949c in M. smegmatis and E. the of Rv2949c, recombinant forms of this produced and Because some the and of mycobacterial proteins have the of recombinant proteins purified from mycobacterial with E. products T. D. M. R. J. Young D. Infect. Immun. PubMed Google Scholar, J.A. Infect. Immun. 1996; PubMed Google Scholar, Triccas J.A. C. Exp. 1996; 103: PubMed Scopus Google Scholar, S. J. J. D. R. R. Infect. PubMed Scopus Google Scholar), both an E. and a M. smegmatis used and the production of Rv2949c in M. the for described was M. smegmatis was with or with the and recombinant on in but the same as not of recombinant Rv2949c of the was by not however, the production of the was found to be as it was of the recombinant in was used of to to the and but the production of recombinant in this was in not with the made on of Rv2949c some on M. which be by the in used to produce Rv2949c, and the recombinant was purified to near from these as described Rv2949c was also produced in E. the Although of the produced was in the the form of not of the recovered in the to the of recombinant Rv2949c from E. forms of recombinant Rv2949c used in enzymatic of Rv2949c as a pyruvate-lyase produces 4-HB by pyruvate from and the catalytic of the recombinant proteins produced in M. smegmatis and in E. coli, an on that for the UbiC of E. was used M. Severin K. Heide L. PubMed Scopus (86) Google Scholar). The of pyruvate from chorismate was a that was not 4-HB formation was also by of chorismate to 4-HB the used in the a not form of purified recombinant Rv2949c or was to the reaction pyruvate was from chorismate to form 4-HB in a The for both enzymes that was on the and The apparent Km for chorismate as 19.7 μm for the recombinant Rv2949c produced in M. smegmatis and as μm for the enzyme produced in E. kcat as 0.102 and These kcat are those for the E. UbiC 2002; PubMed Scopus Google Scholar). pyruvate was the or 4-HB formation was by not The addition of to the reaction a an on the of Rv2949c produced in M. smegmatis that this the E. UbiC has no for not was also and The enzyme was found to be a of and with an not for the UbiC a inhibition was in the of a chorismate to the apparent Km the addition of μm 4-HB to the reaction pyruvate formation by of formation the same was by and chorismate was to and of inhibition in the of chorismate is of a The inhibition of 4-HB was and the inhibition for this was to be to the value for 4-HB of UbiC 2002; PubMed Scopus Google Scholar). In a chorismate of pyruvate not to not in the of the purified recombinant enzymes be for significant of that Rv2949c a chorismate synthase) responsible for the production of 4-HB from chorismate and that it is the sole enzymatic source of this in M. tuberculosis. Rv2949c some sequence similarities with putative chorismate from and but no significant with the chorismate pyruvate-lyase of E. coli, Although the of Rv2949c to be and with that of this to the that these enzymes are of reaction enzymes from F. J. Rev. Microbiol. 2001; PubMed Scopus Google Scholar). it that in M. tuberculosis 4-HB is Although from that 4-HB is the precursor of it that p-HBADs PGL in are the products derived from 4-HB produced by tubercle M. tuberculosis strains are of (2Collins M.D. Jones D. Microbiol. Rev. 1981; 45: 316-354Crossref PubMed Google Scholar), and, to no complex sharing the same aromatic as p-HBADs has been described in this to that all M. tuberculosis strains have the to produce complex The that the mutant not a of 4-HB derivatives in the in physiology of the tubercle The of phenolic glycolipids and the that some of the PGL species produced by M. with M. J. PubMed Scopus Google Scholar) to that these molecules as of of the cell a of the lipid and acid of was in the present to this and, as no or was found the mutant and the we that p-HBADs are to be of envelope A for the of p-HBADs and the of PGL in some M. tuberculosis strains is related to their in glycosylated phenolphthiocerol are only found in a few Mycobacterium M. M. M. tuberculosis, M. M. M. M. M. and M. M. P. 1998; PubMed Google Scholar). the exception of M. all of these species are for Although PGL are known virulence factors of M. leprae roles in the of J. Fujiwara T. Brennan P.J. McNeil M. Turco S.J. Sibille J.-C. Snapper M. Aisen P. Bloom B.R. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 2453-2457Crossref PubMed Scopus (205) Google Scholar, 6Puzo G. Critic. Rev. Microbiol. 1990; 17: 305-327Crossref PubMed Scopus (47) Google Scholar, 7Ng V. Zanazzi G. Timpl R. Talts J.F. Salzer J.L. Brennan P.J. Rambukkana A. Cell. 2000; 103: 511-524Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar, 8Schlesinger L.S. Horwitz M.A. J. Exp. Med. 1991; 174: 1031-1038Crossref PubMed Scopus (67) Google Scholar), for the of 4-HB derivatives to the pathogenesis of tuberculosis has been only was that the and of a of M. tuberculosis was associated with the of PGL in this M.B. Domenech P. Manca C. Su H. Barczak A.K. Kreiswirth B.N. Kaplan G. Barry C.E. II I. Nature. 2004; 431: 84-87Crossref PubMed Scopus (606) Google Scholar). a mutant of M. tuberculosis to be in the production of the and forms of p-HBADs (18Pérez E. Constant P. Lemassu A. Laval F. Daffé M. Guilhot C. J. Biol. Chem. 2004; 279: 42574-42583Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar), a virulence in immunodeficient mice (11Hisert K.B. Kirksey M.A. Gomez J.E. Sousa A.O. Cox J.S. Jr Jacobs W. R. Nathan, C.F. McKinney J.D. Infect. Immun. 2004; 72: 5315-5321Crossref PubMed Scopus (44) Google Scholar). data indicate that a mutant in M. tuberculosis macrophages to cytokines the (10Griffin R. Stadthagen Gomez G. Young D. Coade S. Bottová I. Nigou J. Brando T. Puzo G. Gicquel B. Lowrie D. Jackson M. Tascon R.E. Keystone Symposium, British Columbia, April 2-7, 2005, Bill and Melinda Gates Foundation. Whistler, British Columbia, Canada2005Google Scholar). it is that both p-HBADs and PGL important roles in the of the and that the glycosylated aromatic of these molecules is involved in some of their biological The of a M. tuberculosis mutant of all forms of p-HBADs, provides a to the of these molecules to We C. and I. for their with H. for and K. and K. for of the

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