Occurrence of an antigenic triacyl trehalose in clinical isolates and reference strains of Mycobacterium tuberculosis

Muñoz, Manuel; Lanéelle, Marie‐Antoinette; Luquin, Marina; Torrelles, Jordi B.; Julián, Esther; Ausina, Vicente; Daffé, Mamadou

doi:10.1111/j.1574-6968.1997.tb12781.x

Cited by 26 publications

(22 citation statements)

References 21 publications

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“…In the current model of the mycobacterial outer membrane, the inner leaflet is composed of extremely long-chain mycolic acids, which are covalently attached to the arabinogalactan layer, and the noncovalently associated outer leaflet is dominated by long branched-chain lipids, including di-, tri-, and pentaacyltrehaloses (3,4). Consistent with their surface location, acyltrehaloses have proposed roles in the attachment of the carbohydrate capsule layer and have been identified as antigens, leading to their exploration as serodiagnostic markers with the potential to distinguish between tuberculous and nontuberculous mycobacteria (5)(6)(7)(8).…”

mentioning

confidence: 83%

The rv1184c Locus Encodes Chp2, an Acyltransferase in Mycobacterium tuberculosis Polyacyltrehalose Lipid Biosynthesis

et al. 2015

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Trehalose glycolipids are found in many bacteria in the suborder Corynebacterineae, but methyl-branched acyltrehaloses are exclusive to virulent species such as the human pathogen Mycobacterium tuberculosis. In M. tuberculosis, the acyltransferase PapA3 catalyzes the formation of diacyltrehalose (DAT), but the enzymes responsible for downstream reactions leading to the final product, polyacyltrehalose (PAT), have not been identified. The PAT biosynthetic gene locus is similar to that of another trehalose glycolipid, sulfolipid 1. Recently, Chp1 was characterized as the terminal acyltransferase in sulfolipid 1 biosynthesis. Here we provide evidence that the homologue Chp2 (Rv1184c) is essential for the final steps of PAT biosynthesis. Disruption of chp2 led to the loss of PAT and a novel tetraacyltrehalose species, TetraAT, as well as the accumulation of DAT, implicating Chp2 as an acyltransferase downstream of PapA3. Disruption of the putative lipid transporter MmpL10 resulted in a similar phenotype. Chp2 activity thus appears to be regulated by MmpL10 in a relationship similar to that between Chp1 and MmpL8 in sulfolipid 1 biosynthesis. Chp2 is localized to the cell envelope fraction, consistent with its role in DAT modification and possible regulatory interactions with MmpL10. Labeling of purified Chp2 by an activity-based probe was dependent on the presence of the predicted catalytic residue Ser141 and was inhibited by the lipase inhibitor tetrahydrolipstatin (THL). THL treatment of M. tuberculosis resulted in selective inhibition of Chp2 over PapA3, confirming Chp2 as a member of the serine hydrolase superfamily. Efforts to produce in vitro reconstitution of acyltransferase activity using straight-chain analogues were unsuccessful, suggesting that Chp2 has specificity for native methyl-branched substrates.

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confidence: 83%

The rv1184c Locus Encodes Chp2, an Acyltransferase in Mycobacterium tuberculosis Polyacyltrehalose Lipid Biosynthesis

et al. 2015

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“…2A) [173,178]. In an isolated report [179], triacyl trehaloses (TATs) ( Fig. 2A) were characterised from Mtb.…”

Section: Mycolate Export and Deposition In The Cell Wallmentioning

confidence: 97%

Regulation of Cell Wall Synthesis and Growth

Dover¹,

Alderwick²,

Brown³

et al. 2007

CMM

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The replication and growth of Mycobacterium tuberculosis are fundamentally linked to the synthesis and extension of its complex cell wall. Incorporation of new wall material must be tightly regulated so that its deposition does not compromise the extant structure. M. tuberculosis also produces an impressive array of complex bioactive lipids that are intimately involved in pathogenesis and protective immunity. The profiles of these lipids are regulated appropriately to allow the bacterium to respond to the prevailing conditions it faces in vivo. A number of regulatory strategies employed by M. tuberculosis to control cell wall biosynthesis and cell division have now been elucidated. The review highlights the role of alternative sigma factors with extracytoplasmic function in the activation of genes for biosynthesis of complex lipids involved in pathogenicity. Rel(Mtb) and CRP(Mt) play roles in cell wall responses to general nutrient deprivation by synthesis and sensing of starvation second messengers, respectively. Recently, the importance of protein phosphorylation networks in cell wall biosynthesis has attracted considerable interest. A plethora of two-component and eukaryotic-like serine/threonine protein kinases systems have been discovered and several are implicated in cell-division, morphogenesis and regulation of the profile of complex bioactive lipids elaborated by the pathogen.

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“…Di-, tri-, and polyacylated acyltrehaloses are complex glycolipids containing methyl-branched fatty acids that are located in the outer layer of the mycobacterial cell envelope (54)(55)(56)(57)(58). They appear to be restricted to pathogenic mycobacteria.…”

Section: Polyacylated Trehalosementioning

confidence: 99%

Genetics of Mycobacterial Trehalose Metabolism

Kalscheuer

Koliwer‐Brandl

2014

Microbiol Spectr

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Trehalose [alpha-D-glucopyranosyl-(1→1)-alpha- D-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 de novo 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 Mycobacterium tuberculosis 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 M. tuberculosis.

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Occurrence of an antigenic triacyl trehalose in clinical isolates and reference strains of Mycobacterium tuberculosis

Cited by 26 publications

References 21 publications

The rv1184c Locus Encodes Chp2, an Acyltransferase in Mycobacterium tuberculosis Polyacyltrehalose Lipid Biosynthesis

The rv1184c Locus Encodes Chp2, an Acyltransferase in Mycobacterium tuberculosis Polyacyltrehalose Lipid Biosynthesis

Regulation of Cell Wall Synthesis and Growth

Genetics of Mycobacterial Trehalose Metabolism

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