Biosynthetic origin of mycobacterial cell wall galactofuranosyl residues

Weston, Anthony; Stern, Richard J.; Lee, R.E.; Nassau, Pamela M.; Monsey, D.; Martin, Steve L.; Scherman, Michael S.; Besra, Gurdyal S.; Duncan, Ken; McNeil, Michael

doi:10.1016/s0962-8479(98)80005-1

Cited by 108 publications

(102 citation statements)

References 32 publications

Supporting

Mentioning

102

Contrasting

Order By: Relevance

“…The next two steps occur separately and result in the formation of units that will be polymerized in future steps. In these reactions, UDPgalactofuranose is generated from UDP-galactopyranose (444) and decaprenylphosphoryl-arabinofuranose is generated from the pentose phosphate pathway (366,367). Galactofuranose is then added to the linker region and polymerized to form long, linear chains (281).…”

Section: How Do Mycobacteria Synthesize Cell Wall Components?mentioning

confidence: 99%

Bacterial Growth and Cell Division: a Mycobacterial Perspective

Hett

Rubín

2008

Microbiol Mol Biol Rev

341

293

View full text Add to dashboard Cite

SUMMARY The genus Mycobacterium is best known for its two major pathogenic species, M. tuberculosis and M. leprae, the causative agents of two of the world's oldest diseases, tuberculosis and leprosy, respectively. M. tuberculosis kills approximately two million people each year and is thought to latently infect one-third of the world's population. One of the most remarkable features of the nonsporulating M. tuberculosis is its ability to remain dormant within an individual for decades before reactivating into active tuberculosis. Thus, control of cell division is a critical part of the disease. The mycobacterial cell wall has unique characteristics and is impermeable to a number of compounds, a feature in part responsible for inherent resistance to numerous drugs. The complexity of the cell wall represents a challenge to the organism, requiring specialized mechanisms to allow cell division to occur. Besides these mycobacterial specializations, all bacteria face some common challenges when they divide. First, they must maintain their normal architecture during and after cell division. In the case of mycobacteria, that means synthesizing the many layers of complex cell wall and maintaining their rod shape. Second, they need to coordinate synthesis and breakdown of cell wall components to maintain integrity throughout division. Finally, they need to regulate cell division in response to environmental stimuli. Here we discuss these challenges and the mechanisms that mycobacteria employ to meet them. Because these organisms are difficult to study, in many cases we extrapolate from information known for gram-negative bacteria or more closely related GC-rich gram-positive organisms.

show abstract

Section: How Do Mycobacteria Synthesize Cell Wall Components?mentioning

confidence: 99%

Bacterial Growth and Cell Division: a Mycobacterial Perspective

Hett

Rubín

2008

Microbiol Mol Biol Rev

341

293

View full text Add to dashboard Cite

show abstract

“…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 (10,11). 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 (12,13)) to form polyprenol-P-PGlcNAc-Rha-Gal 30 through a novel enzyme designated GlfT (Rv3808c). This latter enzyme expresses two glycosyltransferase activities, a UDPGalf:␤-D-(135)-Galf and a UDP-Galf:␤-D-(136)-Galf, both activities being required for alternating ␤(135) and ␤(136) linkages during galactan polymerization (11,14).…”

mentioning

confidence: 99%

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

Alderwick

Radmacher

Seidel

et al. 2005

Journal of Biological Chemistry

136

259

View full text Add to dashboard Cite

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.

show abstract

“…This uncommon monosaccharide is highly immunogenic and present in the sur-face glycoconjugates of many pathogenic bacteria, fungi, and protozoan parasites (21). It originates from the action of the UDP-galactopyranose mutase (UGM) that catalyzes the interconversion of UDP-galactopyranose (UDP-Gal p ) into UDP-galactofuranose (UDP-Gal f ) (22)(23)(24)(25)(26). Because Gal f is essential for the survival or virulence of various pathogenic bacteria (27) but is absent from higher eukaryotes, UGM is a recognized drug target and has been extensively studied in prokaryotes (28 -33).…”

mentioning

confidence: 99%

Targeted Gene Deletion of Leishmania major UDP-galactopyranose Mutase Leads to Attenuated Virulence

Kleczka

Lamerz

Zandbergen

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

Considering the high incidence of galactofuranose (Gal f ) in pathogens and its absence from higher eukaryotes, the enzymes involved in the biosynthesis of this unusual monosaccharide appear as attractive drug targets. However, although the importance of Gal f in bacterial survival or pathogenesis is established, its role in eukaryotic pathogens is still undefined. Recently, we reported the identification and characterization of the first eukaryotic UDP-galactopyranose mutases. This enzyme holds a central role in Gal f metabolism by providing UDP-Gal f to all galactofuranosyltransferases. In this work, the therapeutical potential of Gal f metabolism in Leishmania major was hence evaluated by targeted replacement of the GLF gene encoding UDP-galactopyranose mutase. In L. major, Gal f is present in the membrane anchor of the lipophosphoglycan (LPG) and in glycoinositolphospholipids. Accordingly, the generated glf ؊ mutant is deficient in LPG backbone and expresses truncated glycoinositolphospholipids. These structural changes do not influence the in vitro growth of the parasite but lead to an attenuation of virulence comparable with that observed with a mutant exclusively deficient in LPG.

show abstract

Biosynthetic origin of mycobacterial cell wall galactofuranosyl residues

Cited by 108 publications

References 32 publications

Bacterial Growth and Cell Division: a Mycobacterial Perspective

Bacterial Growth and Cell Division: a Mycobacterial Perspective

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

Targeted Gene Deletion of Leishmania major UDP-galactopyranose Mutase Leads to Attenuated Virulence

Contact Info

Product

Resources

About