Deletion of Cg-emb in Corynebacterianeae Leads to a Novel Truncated Cell Wall Arabinogalactan, whereas Inactivation of Cg-ubiA Results in an Arabinan-deficient Mutant with a Cell Wall Galactan Core
The cell wall of Mycobacterium tuberculosis has a complex ultrastructure that consists of mycolic acids connected to peptidoglycan via arabinogalactan (AG) and abbreviated as the mAGP complex. The mAGP complex is crucial for the survival and pathogenicity of M. tuberculosis and is the target of several anti-tubercular agents. Apart from sharing a similar mAGP and the availability of the complete genome sequence, Corynebacterium glutamicum has proven useful in the study of orthologous M. tuberculosis genes essential for viability. Here we examined the effects of particular genes involved in AG polymerization by gene deletion in C. glutamicum. The anti-tuberculosis drug ethambutol is thought to target a set of arabinofuranosyltransferases (Emb) that are involved in arabinan polymerization. Deletion of emb in C. glutamicum results in a slow growing mutant with profound morphological changes. Chemical analysis revealed a dramatic reduction of arabinose resulting in a novel truncated AG structure possessing only terminal arabinofuranoside (t-Araf) residues with a corresponding loss of cell wall bound mycolic acids. Treatment of wild-type C. glutamicum with ethambutol and subsequent cell wall analyses resulted in an identical phenotype comparable to the C. glutamicum emb deletion mutant. Additionally, disruption of ubiA in C. glutamicum, the first enzyme involved in the biosynthesis of the sugar donor decaprenol phosphoarabinose (DPA), resulted in a complete loss of cell wall arabinan. Herein, we establish for the first time, (i) that in contrast to M. tuberculosis embA and embB mutants, deletion of C. glutamicum emb leads to a highly truncated AG possessing t-Araf residues, (ii) the exact site of attachment of arabinan chains in AG, and (iii) DPA is the only Araf sugar donor in AG biosynthesis suggesting the presence of a novel enzyme responsible for “priming” the galactan domain for further elaboration by Emb, resulting in the final maturation of the native AG polysaccharide. The cell wall of Mycobacterium tuberculosis has a complex ultrastructure that consists of mycolic acids connected to peptidoglycan via arabinogalactan (AG) and abbreviated as the mAGP complex. The mAGP complex is crucial for the survival and pathogenicity of M. tuberculosis and is the target of several anti-tubercular agents. Apart from sharing a similar mAGP and the availability of the complete genome sequence, Corynebacterium glutamicum has proven useful in the study of orthologous M. tuberculosis genes essential for viability. Here we examined the effects of particular genes involved in AG polymerization by gene deletion in C. glutamicum. The anti-tuberculosis drug ethambutol is thought to target a set of arabinofuranosyltransferases (Emb) that are involved in arabinan polymerization. Deletion of emb in C. glutamicum results in a slow growing mutant with profound morphological changes. Chemical analysis revealed a dramatic reduction of arabinose resulting in a novel truncated AG structure possessing only terminal arabinofuranoside (t-Araf) residues with a corresponding loss of cell wall bound mycolic acids. Treatment of wild-type C. glutamicum with ethambutol and subsequent cell wall analyses resulted in an identical phenotype comparable to the C. glutamicum emb deletion mutant. Additionally, disruption of ubiA in C. glutamicum, the first enzyme involved in the biosynthesis of the sugar donor decaprenol phosphoarabinose (DPA), resulted in a complete loss of cell wall arabinan. Herein, we establish for the first time, (i) that in contrast to M. tuberculosis embA and embB mutants, deletion of C. glutamicum emb leads to a highly truncated AG possessing t-Araf residues, (ii) the exact site of attachment of arabinan chains in AG, and (iii) DPA is the only Araf sugar donor in AG biosynthesis suggesting the presence of a novel enzyme responsible for “priming” the galactan domain for further elaboration by Emb, resulting in the final maturation of the native AG polysaccharide. The Corynebacterianeae represent a distinct and unusual group within Gram-positive bacteria, with the most prominent members being the human pathogens Mycobacterium tuberculosis and Mycobacterium leprae (1Bloom B.R. Murray C.J. Science. 1992; 257: 1055-1064Crossref PubMed Scopus (1245) Google Scholar). In addition, the human pathogen Corynebacterium diphtheriae is the causal agent of diphtheria, and serious economic losses occur from the infection of animals by corynebacterial strains, such as Corynebacterium pseudotuberculosis and Corynebacterium matruchotii (2Coyle M.B. Lipsky B.A. Clin. Microbiol. Rev. 1990; 3: 227-246Crossref PubMed Scopus (284) Google Scholar, 3Funke G. von Graevenitz A. Clarridge 3rd, J.E. Bernard K.A. Clin. Microbiol. Rev. 1997; 10: 125-159Crossref PubMed Google Scholar). Furthermore, non-pathogenic bacteria belong to this taxon, such as Corynebacterium glutamicum, which is used in the industrial production of amino acids (4Sahm H. Eggeling L. de Graaf A.A. Biol. Chem. 2000; 381: 899-910Crossref PubMed Scopus (128) Google Scholar). A common feature to all these bacteria is that they possess an unusual cell wall matrix composed of mycolic acids, arabinogalactan, and peptidoglycan and is often referred to as the mycolyl-arabinogalactan-peptidoglycan (mAGP) 6The abbreviations used are: mAGP, mycolyl arabinogalactan peptidoglycan; AG, arabinogalactan; Ara, arabinose; CMAME, corynomycolic acid methyl ester; DPA, decaprenol phosphoarabinose; EMB, ethambutol; Gal, galactose; GC, gas chromatography; GC/MS, gas chromatography/mass spectrometry; GlcNAc, N-acetyl-galactosamine; MALDI-TOF, matrix-assisted laser desorption/ionization time-of-flight; Rha, rhamnose; OD, optimal density. complex (5McNeil M. Daffe M. Brennan P.J. J. Biol. Chem. 1990; 265: 18200-18206Abstract Full Text PDF PubMed Google Scholar, 6Besra G.S. Khoo K.H. McNeil M.R. Dell A. Morris H.R. Brennan P.J. Biochemistry. 1995; 34: 4257-4266Crossref PubMed Scopus (210) Google Scholar, 7Daffe M. Brennan P.J. McNeil M. J. Biol. Chem. 1990; 265: 6734-6743Abstract Full Text PDF PubMed Google Scholar, 8McNeil M. Daffe M. Brennan P.J. J. Biol. Chem. 1991; 266: 13217-13223Abstract Full Text PDF PubMed Google Scholar, 9Dover L.G. Cerdeno-Tarraga A.M. Pallen M.J. Parkhill J. Besra G.S. FEMS Microbiol. Rev. 2004; 28: 225-250Crossref PubMed Scopus (96) Google Scholar). Arabinogalactan (AG) plays a crucial role in covalently anchoring the outer lipid layer to peptidoglycan. Synthesis of AG begins with the formation of the linker unit through the transfer of GlcNAc-1-P and Rha from their respective sugar nucleotides (UDP-GlcNAc and dTDP-Rha) to form polyprenol-P-P-GlcNAc and polyprenol-P-P-GlcNAc-Rha lipid intermediates (10Mikusova K. Mikus M. Besra G.S. Hancock I. Brennan P.J. J. Biol. Chem. 1996; 271: 7820-7828Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 11Mikusova K. Yagi T. Stern R. McNeil M.R. Besra G.S. Crick D.C. Brennan P.J. J. Biol. Chem. 2000; 275: 33890-33897Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). The intermediates polyprenol-P-P-GlcNAc and polyprenol-P-P-GlcNAc-Rha then serve as acceptors for the sequential addition of galactofuranose (Galf) residues from UDP-Galf (generated from UDP-Galp via Glf (12Weston A. Stern R.J. Lee R.E. Nassau P.M. Monsey D. Martin S.L. Scherman M.S. Besra G.S. Duncan K. McNeil M.R. Tuber Lung Dis. 1997; 78: 123-131Abstract Full Text PDF PubMed Scopus (103) Google Scholar, 13Sanders D.A. Staines A.G. McMahon S.A. McNeil M.R. Whitfield C. Naismith J.H. Nat. Struct. Biol. 2001; 8: 858-863Crossref PubMed Scopus (149) Google Scholar)) to form polyprenol-P-P-GlcNAc-Rha-Gal30 through a novel enzyme designated GlfT (Rv3808c). This latter enzyme expresses two glycosyltransferase activities, a UDP-Galf:β-d-(1→5)-Galf and a UDP-Galf:β-d-(1→6)-Galf, both activities being required for alternating β(1→5) and β(1→6) linkages during galactan polymerization (11Mikusova K. Yagi T. Stern R. McNeil M.R. Besra G.S. Crick D.C. Brennan P.J. J. Biol. Chem. 2000; 275: 33890-33897Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, 14Kremer L. Dover L.G. Morehouse C. Hitchin P. Everett M. Morris H.R. Dell A. Brennan P.J. McNeil M.R. Flaherty C. Duncan K. Besra G.S. J. Biol. Chem. 2001; 276: 26430-26440Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar). Chemical analysis of the mature lipid-linked galactan, synthesized in vitro (11Mikusova K. Yagi T. Stern R. McNeil M.R. Besra G.S. Crick D.C. Brennan P.J. J. Biol. Chem. 2000; 275: 33890-33897Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar), suggests that this intermediate then serves as the acceptor for the subsequent addition of arabino-furanose (Araf) residues from the arabinose sugar donor β-d-arabino-furanosyl-1-monophosphoryldecaprenol (DPA) in the formation of the Araf portion (α1→5, α1→3, and β1→2 linkages) of AG (15Xin Y. Lee R.E. Scherman M.S. Khoo K.H. Besra G.S. Brennan P.J. McNeil M. Biochim. Biophys. Acta. 1997; 1335: 231-234Crossref PubMed Scopus (28) Google Scholar, 16Wolucka B.A. McNeil M.R. de Hoffmann E. Chojnacki T. Brennan P.J. J. Biol. Chem. 1994; 269: 23328-23335Abstract Full Text PDF PubMed Google Scholar, 17Lee R.E. Brennan P.J. Besra G.S. Glycobiology. 1997; 7: 1121-1128Crossref PubMed Scopus (93) Google Scholar, 18R. E. Lee K.M. Brennan P.J. Besra G.S. J. Am. Chem. Soc. 1995; 117: 11829-11832Crossref Scopus (149) Google Scholar). The intermediate is and to peptidoglycan Besra G.S. Brennan P.J. E. PubMed Scopus (28) Google Scholar, T. K. Crick D.C. Brennan P.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). that of ethambutol to a of mycolic acid transfer to the cell wall and an of and K. K.A. PubMed Scopus Google Scholar). to AG biosynthesis K. PubMed Scopus (284) Google Scholar). The target of the emb in Mycobacterium and M. The consists of in M. Besra G.S. K. Brennan P.J. A. 1996; PubMed Scopus Google and in M. tuberculosis A. C. Nat. 1997; 3: PubMed Scopus Google Scholar). further the role of in arabinan and genes in Mycobacterium Khoo K.H. C. McNeil M.R. Brennan P.J. D. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, McNeil M.R. Khoo K.H. Brennan P.J. D. Microbiol. PubMed Scopus Google Scholar). all only the crucial terminal which is the for in AG, in both embA and embB with the AG structure Khoo K.H. C. McNeil M.R. Brennan P.J. D. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). This that both and are involved in the formation of the terminal in AG, and in the formation of arabinan in McNeil M.R. Khoo K.H. Brennan P.J. D. Microbiol. PubMed Scopus Google Scholar). to deletion of embA and embB in M. tuberculosis in M. to the of cell wall mAGP M. Y. McNeil M. J. 2001; PubMed Scopus Google Scholar, K. M. Stern R.J. Scherman M.S. M. McNeil M. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, C. H.R. H. M. J. 2000; PubMed Scopus Google Scholar). In the study we through analyses the first and of of cell wall arabinan biosynthesis in a and we the of to complex and glutamicum wild-type and referred for the of the as C. and in and The in this study of of of of and of and used a of The used for C. glutamicum L. M. of Corynebacterium glutamicum. Google Scholar). for lipid analyses by an of by a and of C. for lipid and cell wall analysis required two a for which then used to a for This then used to a to which an of used for deletion and as with the gene of the C. glutamicum and M. tuberculosis in The used for deletion of gene to the to the gene in The resulting with and the final by emb the used and the the and used The resulting with to of ubiA an of which and the site of the to of C. glutamicum by for to disruption of ubiA with in the and the from C. and the wild-type and with The resulting a and a with subsequent to with a by with and as that with and and of from C. glutamicum as and by two with of for The bound from the cell by the addition of of of by and and for The and with and in the and in from to and in and acid in to corynomycolic acid methyl and with R. K. Dover L.G. H. T. Besra G.S. Eggeling L. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). of the mAGP in by and G.S. Khoo K.H. McNeil M.R. Dell A. Morris H.R. Brennan P.J. Biochemistry. 1995; 34: 4257-4266Crossref PubMed Scopus (210) Google Scholar, 7Daffe M. Brennan P.J. McNeil M. J. Biol. Chem. 1990; 265: 6734-6743Abstract Full Text PDF PubMed Google Scholar). The with in for to with in and and to a highly cell wall G.S. Khoo K.H. McNeil M.R. Dell A. Morris H.R. Brennan P.J. Biochemistry. 1995; 34: 4257-4266Crossref PubMed Scopus (210) Google Scholar, 7Daffe M. Brennan P.J. McNeil M. J. Biol. Chem. 1990; 265: 6734-6743Abstract Full Text PDF PubMed Google Scholar). of by wall in of acid for as G.S. Khoo K.H. McNeil M.R. Dell A. Morris H.R. Brennan P.J. Biochemistry. 1995; 34: 4257-4266Crossref PubMed Scopus (210) Google Scholar, 7Daffe M. Brennan P.J. McNeil M. J. Biol. Chem. 1990; 265: 6734-6743Abstract Full Text PDF PubMed Google Scholar). residues with of in and the and examined by gas as G.S. Khoo K.H. McNeil M.R. Dell A. Morris H.R. Brennan P.J. 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This is in with the that the genome of Corynebacterium is to represent the of Corynebacterianeae and has a of and gene Y. Y. K. T. PubMed Scopus Google Scholar). the emb of C. glutamicum, a to to embA and embB of and of of C. glutamicum E. Besra G.S. G. H. Eggeling L. PubMed Scopus (96) Google Scholar). In M. leprae and M. the genes are by genes that a and a in these The and the availability of the complete genome of C. glutamicum has proven useful in the study of orthologous M. tuberculosis genes that are essential for viability. in this study we examined the in of arabinan biosynthesis and of the sugar donor DPA, of by gene deletion in C. glutamicum, and disruption of an enzyme to involved in the biosynthesis of the sugar donor of C. emb of C. glutamicum we the gene the of a E. Besra G.S. G. H. Eggeling L. PubMed Scopus (96) Google and a of in presence of E. Besra G.S. G. H. Eggeling L. PubMed Scopus (96) Google Scholar). to to a deletion of emb in C. glutamicum. The to The C. glutamicum and in several of the genome by A and The gene for of a that in the wild-type in of and by in all of the wild-type a of emb by to emb A further of emb deletion in of the in a analysis The of the wild-type is in that of the emb deletion mutant is to which the of emb of This the of the gene in the emb deletion mutant. In of C. deletion mutant with E. Besra G.S. G. H. Eggeling L. PubMed Scopus (96) Google Scholar), and with for L. M. of Corynebacterium glutamicum. Google Scholar). of C. glutamicum an of C. an of of the deletion mutant with the wild-type a of emb to of emb with M. tuberculosis and embB and of of C. by and that with C. glutamicum, C. profound morphological similar to that of C. glutamicum with E. Besra G.S. G. H. Eggeling L. PubMed Scopus (96) Google of the of the C. mutant to the C. and with C. glutamicum for corynomycolic acids. by and the of corynomycolic acid methyl The of the is in In the C. cell corynomycolic acids The of this with to a of cell corynomycolic acids. results that is involved in arabinan biosynthesis of AG deletion the of M. Daffe M. Brennan P.J. J. Biol. Chem. 1991; 266: 13217-13223Abstract Full Text PDF PubMed Google Scholar). of from C. glutamicum, C. and C. analysis of from C. glutamicum cell the presence of arabinose and of M. tuberculosis AG sugar that are with C. glutamicum, with of Rha G.S. Khoo K.H. McNeil M.R. Dell A. Morris H.R. Brennan P.J. Biochemistry. 1995; 34: 4257-4266Crossref PubMed Scopus (210) Google Scholar, 7Daffe M. Brennan P.J. McNeil M. J. Biol. Chem. 1990; 265: 6734-6743Abstract Full Text PDF PubMed Google Scholar). of from C. a with a complete of arabinose in the cell is to that the of Rha is in this mutant. results that the presence of a of Rha in the cell of C. glutamicum is to the arabinan of the cell wall these are of C. glutamicum with of the drug of the emb mutant with the to that of C. glutamicum of from C. glutamicum, C. and C. of C. glutamicum, C. and C. with emb are in linkages in M. tuberculosis and C. glutamicum and The C. glutamicum and M. tuberculosis AG the presence of and residues in C. glutamicum. In C. a loss of and is with only t-Araf residues and results that plays a role in the of AG in to the results with M. and Khoo K.H. C. McNeil M.R. Brennan P.J. D. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar), suggesting of and in the M. emb disruption Khoo K.H. C. McNeil M.R. Brennan P.J. D. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). In addition, the AG of C. glutamicum is unusual in that that the arabinan are by residues, these are in the C. mutant. of the emb mutant with the to that of C. glutamicum. analysis of C. glutamicum with of a comparable to that of C. of from C. from C. and by and the are in The of to an AG with truncated arabinan The and are with an AG and The to AG an Rha resulting from the the the galactan the to by The A of the is in and the of Rha are in the that a galactan from the Rha and that the first the with further the and results are by from by of the resulting The resulting from the of the by resulting from cell from C. of Ara, Gal, and Rha their by of Ara, Gal, and Rha their by of Ara, Gal, and Rha their by of Ara, Gal, and Rha their by analysis in a analysis of cell from C. glutamicum with revealed a similar to that for cell from C. In addition, that C. glutamicum with an AG, which the as in C. the effects of and emb deletion are of by a and the that involved in DPA formation from and decaprenol The ubiA gene is in Corynebacterianeae in within the of cell genes The of M. tuberculosis in C. glutamicum is and during of this to the first of DPA biosynthesis from and decaprenol H. Scherman M.S. D. M. Crick D.C. McNeil M.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). ubiA of C. glutamicum, and C. glutamicum to The resulting by analysis to ubiA This C. similar to C. and of bound cell wall corynomycolic acids and of from C. analysis of the resulting cell wall of C. in contrast to C. revealed a complete of arabinan The results a role of in cell wall arabinan biosynthesis H. Scherman M.S. D. M. Crick D.C. McNeil M.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and that DPA is the donor of Araf residues in cell wall biosynthesis in of the galactan form C. by revealed a of with a galactan residues as for the emb deletion mutant The and the and The to galactan Rha Gal, the to The mAGP of the most cell wall of members of the and is essential for the of M. tuberculosis M. Y. McNeil M. J. 2001; PubMed Scopus Google Scholar, K. M. Stern R.J. Scherman M.S. M. McNeil M. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, C. H.R. H. M. J. 2000; PubMed Scopus Google Scholar). as a peptidoglycan and the mycolic acid Furthermore, biosynthesis is the target of the drug the complete and the involved in AG biosynthesis are L.G. Cerdeno-Tarraga A.M. Pallen M.J. Parkhill J. Besra G.S. FEMS Microbiol. 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Science. 1997; 276: PubMed Scopus Google Scholar). a the of an cell wall mutant in M. tuberculosis with this in and C. glutamicum only a emb we to an emb deletion mutant of C. glutamicum. The deletion mutant a slow growing phenotype with profound morphological changes. analysis of the corynomycolic acid of C. that a complete of cell wall bound that a loss of corynomycolic acid in the with the loss of the terminal and we in contrast to M. embA and embB Khoo K.H. C. McNeil M.R. Brennan P.J. D. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google a loss of cell wall with all and residues the being in the cell wall of the C. with the of The of Araf residues as t-Araf Furthermore, the AG from C. by and acid for the first the of the of A galactan from the Rha and the first the with further the and residues The of t-Araf residues in C. has thought that the gene of embA and embB in are responsible for arabinan the of arabinan an galactan suggests that an responsible for the addition of the the galactan is to that this the arabinan the galactan for further elaboration by emb the of C. glutamicum with results in a phenotype that is identical to the C. with loss of corynomycolic acids and a arabinan in results that emb is the target for and that the of the “priming” enzyme the of AG in M. tuberculosis and is to that this “priming” enzyme an to as a drug disruption in a cell to the presence of t-Araf residues in the of C. glutamicum, we to genes responsible for DPA with the of in C. glutamicum for further This to the that the Emb, which DPA as a sugar an sugar donor 1994; Google Scholar, K. 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PubMed Scopus Google Scholar), and a the In analysis of the of which to involved in cell wall resulted in the of a The ubiA gene to in the genome of C. glutamicum to the gene responsible for galactan biosynthesis and the ubiA is common to all is in bacteria and with the M. tuberculosis of and with of P. M. D. K. M. M. Microbiol. 1996; PubMed Scopus Google Scholar, P. M. M. Microbiol. 1997; PubMed Scopus Google Scholar). that is involved in the first of DPA biosynthesis from and decaprenol H. Scherman M.S. D. M. Crick D.C. McNeil M.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of ubiA is a gene to a which and then is to DPA via an J. The of a ubiA mutant of C. glutamicum and analysis of the cell wall revealed a complete loss of arabinan and a of C. glutamicum. a we that DPA is the only arabinan donor for AG biosynthesis the of arabinose as a drug target to the of to DPA and arabinan. a disruption in a cell wall in such as M. In C. glutamicum and M. tuberculosis a common cell wall ultrastructure and the deletion of emb and disruption of ubiA in C. glutamicum, has to further the role of these genes in cell wall AG biosynthesis in Corynebacterianeae such as Mycobacterium for