Chapter 27 : Genetics of Mycobacterial Arabinogalactan and Lipoarabinomannan Assembly

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The cell wall of is unique in that it differs significantly from both Gram-negative and Gram-positive bacteria. The thick, carbohydrate- and lipid-rich cell wall with distinct lipoglycans enables mycobacteria to survive under hostile conditions such as shortage of nutrients and antimicrobial exposure. The key features of this highly complex cell wall are the mycolyl-arabinogalactan-peptidoglycan (mAGP)–based and phosphatidyl--inositol–based macromolecular structures, with the latter possessing potent immunomodulatory properties. These structures are crucial for the growth, viability, and virulence of and therefore are often the targets of effective chemotherapeutic agents against tuberculosis (TB). Over the past decade, sophisticated genomic and molecular tools have advanced our understanding of the primary structure and biosynthesis of these macromolecules ( ). The availability of the full-genome sequences of various mycobacterial species, including ( ), ( ), and BCG ( ), have greatly facilitated the identification of large numbers of drug targets and antigens specific to TB. Techniques to manipulate mycobacteria have also improved extensively; the conditional expression-specialized transduction essentiality test (CESTET) is currently used to determine the essentiality of individual genes ( ). Finally, various biosynthetic assays using either purified proteins or synthetic cell wall acceptors have been developed to study enzyme function. This article focuses on the recent advances in determining the structural details and biosynthesis of arabinogalactan (AG), lipoarabinomannan (LAM), and related glycoconjugates.

Citation: Jankute M, Grover S, Birch H, Besra G. 2014. Genetics of Mycobacterial Arabinogalactan and Lipoarabinomannan Assembly, p 535-557. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0013-2013
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Figure 1

Schematic structure of mycobacterial arabinogalactan (AG). A linkage unit, composed of rhamnose and -acetyl-glucosamine residues, anchors the whole AG structure to peptidoglycan. The galactan domain is composed of alternating β(1→5) and β(1→6) galactofuranose residues with three chains of arabinan attached to each linear galactan chain at positions 8, 10, and 12. The highly branched nonreducing end of AG terminates with a hexa-arabinofuranoside motif, two-thirds of which is substituted with mycolic acids.

Citation: Jankute M, Grover S, Birch H, Besra G. 2014. Genetics of Mycobacterial Arabinogalactan and Lipoarabinomannan Assembly, p 535-557. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0013-2013
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Figure 2

The biosynthesis of sugar donors required for mycobacterial AG biosynthesis. Both UDP-GlcNAc and dTDP-Rha are utilized in the formation of the linkage unit. UDP-Gal is the sugar donor of the galactofuranosyl residues used in the galactan chain formation. Decaprenylphosphoryl--arabinofuranose (DPA) is the only known high-energy nucleotide providing arabinofuranosyl residues to the arabinan domain of AG.

Citation: Jankute M, Grover S, Birch H, Besra G. 2014. Genetics of Mycobacterial Arabinogalactan and Lipoarabinomannan Assembly, p 535-557. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0013-2013
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Figure 3

Schematic representation of mycobacterial arabinogalactan biosynthesis. WecA catalyzes the transfer of GlcNAc to decaprenyl phosphate, which is then used as an acceptor for addition of rhamnosyl residue by WbbL, thereby forming the full linkage unit. The first two galactofuranosyl (Gal) residues are added to the linkage unit via GlfT1. The bifunctional GlfT2 adds the remaining Gal residues forming a linear galactan chain. Before the polymerization with arabinofuranosyl (Ara) residues, the galactan domain is thought to be translocated across the plasma membrane by the unknown flippase. AftA initiates the transfer of Ara residues from the sugar donor DPA to the 8th, 10th and 12th β(1→6)-linked Gal residues of the galactan chain. EmbA and EmbB proteins act as α-1,5-arabinosyltransferases utilizing the same nucleotide donor DPA. The 3,5-linked Ara branching is introduced by AftC and AftD enzymes. Finally, the terminal Ara residues are added to the arabinan domain by a “capping” enzyme AftB.

Citation: Jankute M, Grover S, Birch H, Besra G. 2014. Genetics of Mycobacterial Arabinogalactan and Lipoarabinomannan Assembly, p 535-557. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0013-2013
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Figure 4

Structure of LM and LAM. The PI-based glycolipids LM and LAM consist of 20 to 30 mannose residues that form the mannose core. This mannose core is futher glycosylated with 55 to 70 arabinose residues arranged in hexa or tetra-motifs that form the arabinan domain of LAM. The terminal arabinose residues in LAM serve as the sites for attachment of mannose residues or phosphatidyl inositol, thus forming the Man-LAM and PI-LAM. These arabinose residues, if uncapped, form the Ara-LAM.

Citation: Jankute M, Grover S, Birch H, Besra G. 2014. Genetics of Mycobacterial Arabinogalactan and Lipoarabinomannan Assembly, p 535-557. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0013-2013
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Figure 5

Biosynthesis of phosphatidyl inositol anchor and sugar donors involved in synthesis of PIMs, LM, and LAM. The synthesis of precursor molecules and sugar donors of the LAM biosynthesis pathway uses the products of the glycolytic pathway. However, the mannose utilized in the synthesis of GDP-Man and PPM can also be exogenously obtained. The pathway for PPM and GDP-Man biosynthesis is interlinked because the prenyl-based sugar donor PPM is synthesized by direct transfer of mannose from GDP-Man to the prenyl phosphate mediated by Ppm1 (). The PI anchor on which the PIMs, LM, and LAM are based is synthesized by transfer of inositol to CDP-DAG, a reaction catalyzed by PgsA ().

Citation: Jankute M, Grover S, Birch H, Besra G. 2014. Genetics of Mycobacterial Arabinogalactan and Lipoarabinomannan Assembly, p 535-557. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0013-2013
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Figure 6

Biosynthesis of PIMs. The PI anchor synthesized by PgsA undergoes multiple mannosylations to produce PIMs. Of the PIM species synthesized, AcPIM and AcPIM are the most abundant. The production of AcPIM serves as the branch point in the PIM biosynthesis, with one branch leading to formation of higher PIM species such as AcPIM and the other leading to LM and LAM production. The AcPIM is synthesized by the mannosyltransferases PimC and/or PimD, both of which remain unidentified. The flippase required for translocating the AcPIM from the cytosolic to extracellular side is also unknown.

Citation: Jankute M, Grover S, Birch H, Besra G. 2014. Genetics of Mycobacterial Arabinogalactan and Lipoarabinomannan Assembly, p 535-557. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0013-2013
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Figure 7

Biosynthesis of LM and LAM. Hyperglycosylation of AcPIM produces LM and LAM. The mannosyltransferases MptB, MptA, and MptC are involved in the synthesis of the mannan core, while the arabinosyltransferases EmbC, AftC, and AftD and an unknown transferase are responsible for the synthesis of the arabinan domain. The arabinan in LAM is capped with mannose residues in at the nonreducing termini referred to as Man-LAM. The enzymes, MptC and CapA, mediate this reaction.

Citation: Jankute M, Grover S, Birch H, Besra G. 2014. Genetics of Mycobacterial Arabinogalactan and Lipoarabinomannan Assembly, p 535-557. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0013-2013
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