Recent advances in mycobacterial cell wall glycan biosynthesis

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The cell wall of mycobacteria, including the causative agents of the human diseases tuberculosis (Mycobacterium tuberculosis) and leprosy (M. leprae), is composed of an array of carbohydrate-containing molecules. These glycoconjugates are assembled by glycosyltransferases (GTs) that work in tandem through pathways that are only now beginning to be fully understood. Given the essentiality of cell wall glycans to mycobacterial viability, these enzymes represent novel targets for drug action. Summarized here are recent genetic and biochemical studies leading to the identification and characterization of mycobacterial GTs.

Introduction

Many mycobacterial species are nonpathogenic organisms but others cause important diseases [1]. Mycobacterium tuberculosis causes tuberculosis (TB), whereas M. leprae is the causative agent of leprosy. In addition, immunocompromised individuals, for example, those that are HIV+, are susceptible to infections by ‘atypical’ mycobacteria, such as M. avium-intracellulare complex (MAC) [2]. Treatments for these diseases are available; however, they require long drug regimens involving multiple antibiotics [3]. Such treatments are made necessary mainly because of the unusual structure of the mycobacterial cell wall, which protects the organism from the immune system of the host, and serves as a formidable barrier to the passage of drugs [4]. Formation of an intact cell wall is required for mycobacterial viability; therefore, the enzymes involved in its assembly are attractive sites for drug action. The increasing incidence of drug-resistant mycobacteria, including extreme drug-resistant TB [5] has underscored the need for new antimycobacterial agents and prompted growing interest in mycobacterial cell wall biosynthesis.

The major entities of the mycobacterial cell wall are two lipidated polysaccharides, the mycolyl-arabinogalactan (mAG) complex and lipoarabinomannan (LAM) [4]. Additional components are a number of glycolipids  lipomannan (LM), phosphatidyl-myo-inositol mannosides (PIMs), phenolic glycolipids (PGLs), and glycopeptidolipids (GPLs)  which are found intercalated within the mAG and LAM. A capsule-like α-glucan is located at the outer periphery of the cell wall.

Following the Herculean task of determining the structure of the mycobacterial cell wall [4], significant attention has been focused on unraveling the biosynthetic pathways that assemble the constituent glycoconjugates [6••]. Although much progress has been made, tremendous challenges remain. Key to the assembly of these complex macromolecules is an array of glycosyltransferases (GTs), which are now being identified and characterized. Given the important roles of these glycoconjugates for mycobacterial viability and virulence [4], inhibitors of these GTs are potential novel drugs for the treatment of diseases such as TB and leprosy [7, 8]. We highlight here recent research on the GTs involved in mycobacterial cell wall assembly. The focus is on work appearing since a review published in 2007, which provided a comprehensive overview of these enzymes [6••].

Section snippets

Synthesis of PIM2 by the α-mannosyltransferases (ManTs) PimA and PimB′

LAM is an important immunomodulatory molecule [9] and the pathway proposed for its assembly in 1997 [10] has been shown to be, in general terms, correct. The reducing end of LAM shares structural similarities with PIMs and LM; all three contain a phosphatidyl inositol (PI) moiety mannosylated at C-2 and C-6 (Figure 1) [4, 9]. LAM is further elaborated by an α-(1→6)-linked-mannopyranose (Manp) domain, functionalized with single α-(1→2)-Manp residues. Attached to this mannan core is an arabinan

GTs involved in other cell wall glycoconjugate synthesis

The biosynthetic pathways of other mycobacterial cell wall glycoconjugates have been less studied. Nevertheless, an increasing amount of work is being done in this area.

Conclusions

AG, LAM, and other glycoconjugates are important components of the mycobacterial cell wall, and are essential for the viability and virulence of these organisms. Although recent investigations have provided a better picture of mycobacterial cell wall assembly, questions remain. For example, many of the biosynthetic GTs still need to be identified and their precise functions/roles must be defined. Considering the complexity of the glycans found in the mycobacterial cell wall, it is clear that

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank the Natural Sciences and Engineering Research Council of Canada and the Alberta Ingenuity Centre for Carbohydrate Science for support.

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