Occurrence of 3‐Oxo‐acyl Groups in the 6,6′‐Diesters of α‐<scp>d</scp>‐Trehalose

Puzo, Germain; Tissié, G.; Aurelle, Hélène; Lacave, Charlotte; Promé, Jean‐Claude

doi:10.1111/j.1432-1033.1979.tb13166.x

Cited by 18 publications

(6 citation statements)

References 16 publications

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“…180±182 These workers reported that the dehydro product was in the form of an ester of trehalose but trehalose does not appear to be required for, nor is it stimulatory to, the cell-free activity 180,183,184 and such esters of the dehydrocorynomycolate are rapidly degraded back to palmitic acid. 185 The nature of the carrier immediately following the condensation remains unclear. Datta and Takayama characterized a phospholipid which contained dehydrocorynomycolate from large-scale cell-free incubations but were unable to conclusively identify this material.…”

Section: The Condensation and Carriersmentioning

confidence: 99%

Mycolic acids: structure, biosynthesis and physiological functions

Barry¹,

Lee²,

Mdluli³

et al. 1998

Progress in Lipid Research

506

495

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Section: The Condensation and Carriersmentioning

confidence: 99%

Mycolic acids: structure, biosynthesis and physiological functions

Barry¹,

Lee²,

Mdluli³

et al. 1998

Progress in Lipid Research

506

495

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“…The mycobacterial Pks13 enzyme was shown to be able to use these short substrates in a recombinant Corynebacterium strain to synthesize mycolic acids in vivo . Published data have suggested that a,a-D-trehalose or D-glucose play a role in the biosynthesis of mycolic acids (Promé et al, 1974;Puzo et al, 1979;Shimakata et al, 1986), and a more recent report has shown the requirement of trehalose (Tropis et al, 2005). In order to seek for their potential involvement during the condensation reaction catalyzed by Pks13, assays supplemented with these sugars were realized.…”

Section: Pks13 Generates Polyol Derivativesmentioning

confidence: 99%

“…AKA: a-alkyl b-ketoacid. Note that spot b was identified as (a-myristyl b-ketopalmitoyl),palmitoyl trehalose by MALDI-TOF MS (monosodium adduct at m/z: 1051.75; theoretical m/z value: 1051.76); the C 16 chain might come from the degradation of an a-alkyl b-ketoacyl chain linked to trehalose by intramolecular retro-Claisen reaction as described previously (Puzo et al, 1979). The minor radiolabeled spots are not linked to the condensation activity.…”

Section: Chemistry and Biologymentioning

confidence: 99%

The Polyketide Synthase Pks13 Catalyzes a Novel Mechanism of Lipid Transfer in Mycobacteria

Gavalda

Bardou

Laval

et al. 2014

Chemistry & Biology

131

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Mycolate-containing compounds constitute major strategic elements of the protective coat surrounding the tubercle bacillus. We have previously shown that FAAL32-Pks13 polyketide synthase catalyzes the condensation reaction, which produces α-alkyl β-ketoacids, direct precursors of mycolic acids. In contrast to the current biosynthesis model, we show here that Pks13 catalyzes itself the release of the neosynthesized products and demonstrate that this function is carried by its thioesterase-like domain. Most importantly, in agreement with the prediction of a trehalose-binding pocket in its catalytic site, this domain exhibits an acyltransferase activity and transfers Pks13's products onto an acceptor molecule, mainly trehalose, leading to the formation of the trehalose monomycolate precursor. Thus, this work allows elucidation of the hinge step of the mycolate-containing compound biosynthesis pathway. Above all, it highlights a unique mechanism of transfer of polyketide synthase products in mycobacteria, which is distinct from the conventional intervention of the discrete polyketide-associated protein (Pap)-type acyltransferases.

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“…The major TDCM (22, Figure 15) contains a C32 corynomycolic acid, however, TDCMs with shorter acid chains (C24-C30) have also been found in Corynebacteria. TDCMs were first isolated in 1963, 77 and later found to be a mixture 78,79 which were separable once converted to their trimethylsilyl derivatives. 78 In more recent years, the isolation, and characterisation of TDCM (22) and mono-corynomycolate from…”

Section: 53a Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Trehalose Glycolipids

Khan¹

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<p>Numerous α,α-trehalose diesters have been isolated from bacteria such as Mycobacteria and Corynebacteria, and more recently from Caenorhabditis elegans dauer larvae. Although these glycolipids are thought to confer protection to the bacteria and larvae against harsh environmental conditions, it is the biological activities of these compounds, including anti-tumour and adjuvant activities, which have been of major interest to scientists over recent years. In this thesis, three different aspects relating to the synthesis and testing of defined trehalose glycolipids will be presented. First, the synthesis of a variety of fatty acid trehalose diesters (TDEs) with varying lipid lengths was performed and the ability of these glycolipids to activate macrophages was studied. Two different synthetic strategies were employed to attain the TDEs of interest and it was observed that lipid lengths of more than 18 carbons were required for macrophage activation. Furthermore, the C22 fatty acid trehalose monoester (TME) and the C26 TME were also synthesised and interestingly they both showed macrophage activation abilities, with subsequent studies indicating that like TDEs, the TMEs were also ligands for mincle, a C-type lectin found on macrophages. This is the first time that TMEs have been tested for their ability to activate macrophages via Mincle. The cytotoxicity of these compounds and subsequent anti-tumour activity of a few selected compounds were also studied and although the TDEs and TMEs did not exhibit any significant cytotoxicity, in in vivo models the C10 TDE and C22 TDE both showed anti-tumour activity. This depicts that the mechanism for anti-tumour activity of these compounds is not due to cytotoxicity but due to as yet unidentified pathway. Methodology that can be applied to the synthesis of more complex trehalose glycolipids, such as trehalose dicorynomycolates (TDCMs, isolated from Corynebacteria) and trehalose dimycolates (TDMs, isolated from Mycobacteria) was also explored. One of the key steps frequently used in the synthesis of these glycolipids is the Fráter-Seebach alkylation. To improve the efficacy of this methodology allylic iodides, rather than alkyl iodides were used for theα-alkylation of β-hydroxy esters. Our results showed that for all substrates studied, the yield of the α-alkylation was greatly improved when the allylic, rather that the alkyl halide was used. The use of this methodology in the synthesis of trehalose monocorynomycolate (TMCM) was also investigated. The third aspect of this thesis focuses on the use of Affinity Based Proteome Profiling (AƒBPP) for elucidating the receptors that TDMs bind to upon interacting with host cell. AƒBPP focuses on using small molecules which mimic the natural substrate for a particular protein and through the use of ‘trap’ and ‘tag’ groups on the molecule the identity of the protein/receptors can be determined. The synthesis of a TDM probe containing a benzophenone ‘trap’ group and an alkyne ‘tag’ group will be discussed.</p>

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Occurrence of 3‐Oxo‐acyl Groups in the 6,6′‐Diesters of α‐d‐Trehalose

Cited by 18 publications

References 16 publications

Mycolic acids: structure, biosynthesis and physiological functions

Mycolic acids: structure, biosynthesis and physiological functions

The Polyketide Synthase Pks13 Catalyzes a Novel Mechanism of Lipid Transfer in Mycobacteria

Synthesis and Biological Evaluation of Trehalose Glycolipids

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