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Genetics of Mycobacterial Trehalose Metabolism

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  • Authors: Rainer Kalscheuer1, Hendrik Koliwer-Brandl2
  • Editors: Graham F. Hatfull3, William R. Jacobs Jr.4
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Institute for Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Duesseldorf, Universitaetsstr. 1, 40225 Duesseldorf, Germany; 2: Institute for Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Duesseldorf, Universitaetsstr. 1, 40225 Duesseldorf, Germany; 3: University of Pittsburgh, Pittsburgh, PA; 4: Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY
  • Source: microbiolspec May 2014 vol. 2 no. 3 doi:10.1128/microbiolspec.MGM2-0002-2013
  • Received 29 August 2013 Accepted 04 September 2013 Published 23 May 2014
  • R. Kalscheuer, rainer.kalscheuer@med.uni-duesseldorf.de
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  • Abstract:

    Trehalose [alpha--glucopyranosyl-(1→1)-alpha--glucopyranoside] is a highly abundant disaccharide in mycobacteria that fulfills many biological roles and has a plethora of possible metabolic fates. Trehalose is synthesized in mycobacteria either from glycolytic intermediates or from alpha-glucans via two alternative routes, the OtsA-OtsB and the TreY-TreZ pathways, respectively. Intracellular trehalose can serve as an endogenous remobilizable carbon storage compound and as a biocompatible stress protectant. Furthermore, trehalose functions as the sugar core of many glycolipids with important structural or immunomodulatory functions such as the cord factor trehalose dimycolate, sulfolipids, and polyacyltrehalose. Moreover, trehalose plays a central role in the formation of the mycolic acid cell wall layer because it serves as a carrier molecule that shuttles mycolic acids in the form of the glycolipid trehalose monomycolate between the cytoplasm and the periplasm. In this process, a specific importer recycles the free trehalose that is extracellularly released as a by-product during mycolate processing via the antigen 85 complex, which might represent a specific adaptation to the intracellular lifestyle of with limited carbohydrate availability. Finally, trehalose is converted to glycogen-like branched alpha-glucans by a four-step metabolic pathway involving the essential maltosyltransferase GlgE, which may be further processed to derivatives with intracellular or extracellular destinations such as polymethylated lipopolysaccharides or capsular alpha-glucans, respectively. In this article we summarize the current knowledge of the genetic basis of trehalose biosynthesis and metabolism in mycobacteria, the biological functions of trehalose-based molecules, and their roles in virulence of the human pathogen .

  • Citation: Kalscheuer R, Koliwer-Brandl H. 2014. Genetics of Mycobacterial Trehalose Metabolism. Microbiol Spectrum 2(3):MGM2-0002-2013. doi:10.1128/microbiolspec.MGM2-0002-2013.

Key Concept Ranking

Acyl Coenzyme A
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Bacteria and Archaea
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Cell Wall Biosynthesis
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2014-05-23
2017-07-27

Abstract:

Trehalose [alpha--glucopyranosyl-(1→1)-alpha--glucopyranoside] is a highly abundant disaccharide in mycobacteria that fulfills many biological roles and has a plethora of possible metabolic fates. Trehalose is synthesized in mycobacteria either from glycolytic intermediates or from alpha-glucans via two alternative routes, the OtsA-OtsB and the TreY-TreZ pathways, respectively. Intracellular trehalose can serve as an endogenous remobilizable carbon storage compound and as a biocompatible stress protectant. Furthermore, trehalose functions as the sugar core of many glycolipids with important structural or immunomodulatory functions such as the cord factor trehalose dimycolate, sulfolipids, and polyacyltrehalose. Moreover, trehalose plays a central role in the formation of the mycolic acid cell wall layer because it serves as a carrier molecule that shuttles mycolic acids in the form of the glycolipid trehalose monomycolate between the cytoplasm and the periplasm. In this process, a specific importer recycles the free trehalose that is extracellularly released as a by-product during mycolate processing via the antigen 85 complex, which might represent a specific adaptation to the intracellular lifestyle of with limited carbohydrate availability. Finally, trehalose is converted to glycogen-like branched alpha-glucans by a four-step metabolic pathway involving the essential maltosyltransferase GlgE, which may be further processed to derivatives with intracellular or extracellular destinations such as polymethylated lipopolysaccharides or capsular alpha-glucans, respectively. In this article we summarize the current knowledge of the genetic basis of trehalose biosynthesis and metabolism in mycobacteria, the biological functions of trehalose-based molecules, and their roles in virulence of the human pathogen .

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FIGURE 1

Trehalose biosynthesis pathways in mycobacteria. Trehalose is synthesized either from glycolytic intermediates via the OtsA-OtsB pathway or from alpha-glucans via the TreY-TreZ pathway. UDP-glucose is formed from glucose-1-phosphate by the UTP-glucose-1-phosphate uridylyltransferase GalU (not depicted). This reaction, however, is not specific for trehalose biosynthesis. doi:10.1128/microbiolspec.MGM2-0002-2013.f1

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FIGURE 2

Structure of the cord factor trehalose-6,6′-dimycolate. In this example, cyclopropanated alpha- and ketomycolates are illustrated. doi:10.1128/microbiolspec.MGM2-0002-2013.f2

Source: microbiolspec May 2014 vol. 2 no. 3 doi:10.1128/microbiolspec.MGM2-0002-2013
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FIGURE 3

Biosynthesis of the major sulfolipid SL-1 and of polyacyltrehalose (PAT). The synthesis of SL-1 and PAT is initiated by sulfation or acylation, respectively, at the 2-position of trehalose. The proposed reaction steps are depicted. Molecular organization of the SL-1 and PAT biosynthesis gene clusters in . doi:10.1128/microbiolspec.MGM2-0002-2013.f3

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FIGURE 4

Model of trehalose as a carrier molecule for mycolic acids in the fomation of the mycobacterial cell wall. Mycolic acids synthesized in the cytoplasm are first conjugated to trehalose and then exported as TMM via the transporter MmpL3. Extracellularly, TMM serves as the substrate of the antigen 85 complex comprising the mycolyltransferases FbpA-C, which transfer the mycolate moiety either to the arabinogalactan layer or to another TMM molecule, yielding cell-wall-bound mycolates or TDM, respectively. The released trehalose moiety of TMM is recycled by the ABC transporter LpqY-SugABC. A putative porin might facilitate transport across the mycomembrane for uptake of exogenous trehalose. doi:10.1128/microbiolspec.MGM2-0002-2013.f4

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FIGURE 5

Conversion of trehalose to alpha-glucans. Trehalose is reversibly interconverted by the trehalose synthase TreS to α-maltose, which is subsequently phosphorylated to α-maltose-1-phosphate by the maltokinase Pep2. Maltose-1-phosphate serves as the activated donor substrate for the maltosyltransferase GlgE producing linear α-1,4-glucans by elongating the nonreducing end of an α-glucan acceptor molecule. Finally, the branching enzyme GlgB introduces α-1,6-linked branches into the linear molecule. doi:10.1128/microbiolspec.MGM2-0002-2013.f5

Source: microbiolspec May 2014 vol. 2 no. 3 doi:10.1128/microbiolspec.MGM2-0002-2013
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