Asymmetric synthesis and structure elucidation of a glycerophospholipid from Mycobacterium tuberculosis

Horst, Bjorn ter; Seshadri, Chetan; Sweet, Lindsay; Young, David C.; Feringa, Ben L.; Moody, D. Branch; Minnaard, Adriaan J.

doi:10.1194/jlr.m001982

Cited by 21 publications

(15 citation statements)

References 43 publications

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“…Okuyama et al showed that palmitic, hexadecenoic, octadecenoic and tuberculostearic acids were the major acids found in mycobacterial phospholipids 33 . Tuberculostearic acid has also been found in the mycobacterial cell wall bound to various lipids, such as glycerolipids 34 or phosphoinositides 35,36 . This reduction in phospholipids correlates with the results of the HPLC analysis, which showed a decrease in palmitic and tuberculostearic acids.…”

Section: Resultsmentioning

confidence: 99%

Mycobacterium tuberculosis is extraordinarily sensitive to killing by a vitamin C-induced Fenton reaction

et al. 2013

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Drugs that kill tuberculosis more quickly could shorten chemotherapy significantly. In Escherichia coli, a common mechanism of cell death by bactericidal antibiotics involves the generation of highly reactive hydroxyl radicals via the Fenton reaction. Here we show that vitamin C, a compound known to drive the Fenton reaction, sterilizes cultures of drug-susceptible and drug-resistant Mycobacterium tuberculosis, the causative agent of tuberculosis. While M. tuberculosis is highly susceptible to killing by vitamin C, other Gram-positive and Gram-negative pathogens are not. The bactericidal activity of vitamin C against M. tuberculosis is dependent on high ferrous ion levels and reactive oxygen species production and causes a pleiotropic effect affecting several biological processes. This study enlightens the possible benefits of adding vitamin C to an anti-tuberculosis regimen and suggests that the development of drugs that generate high oxidative burst could be of great use in tuberculosis treatment.

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Section: Resultsmentioning

confidence: 99%

Mycobacterium tuberculosis is extraordinarily sensitive to killing by a vitamin C-induced Fenton reaction

et al. 2013

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“…After visualization with water spray, 10 bands were scraped and extracted from the silica gel with chloroform/methanol (1:2, vol/vol) and stored at −20°C. Synthesis of C32 PM, C30 mannosyl β-PM, C35 MPD, C35 phosphodolichol, all-S α and β anomeric C32 mannosyl PM, and C19:0/C16:0 phosphatidylethanolamine (TBSA) were accomplished previously or with new methods based on those from prior studies (Moody et al, 2000; van Summeren et al, 2006; Ter Horst et al, 2010). Synthetic preparations of the following lipids were commercially obtained (Avanti Polar Lipids): C18:1/C18:0 phosphatidic acid, C18:0/C18:1 phosphatidylglycerol, C16:0/C16:0 phosphatidylinositol, C18:0/C18:1 phosphatidylserine, C18:1 lyso-phosphatidic acid, C18:0 lyso-phosphatidylglycerol, C18:0 lyso-phosphatidylinositol, C18:0 lyso-phosphatidylserine, and C26:0 lyso-phosphatidylcholine.…”

Section: Methodsmentioning

confidence: 99%

CD1c tetramers detect ex vivo T cell responses to processed phosphomycoketide antigens

Kasmar

Cheng

et al. 2013

Journal of Experimental Medicine

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139

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CD1c is expressed with high density on human dendritic cells (DCs) and B cells, yet its antigen presentation functions are the least well understood among CD1 family members. Using a CD1c-reactive T cell line (DN6) to complete an organism-wide survey of M. tuberculosis lipids, we identified C32 phosphomycoketide (PM) as a previously unknown molecule and a CD1c-presented antigen. CD1c binding and presentation of mycoketide antigens absolutely required the unusual, mycobacteria-specific lipid branching patterns introduced by polyketide synthase 12 (pks12). Unexpectedly, one TCR responded to diversely glycosylated and unglycosylated forms of mycoketide when presented by DCs and B cells. Yet cell-free systems showed that recognition was mediated only by the deglycosylated phosphoantigen. These studies identify antigen processing of a natural bacterial antigen in the human CD1c system, indicating that cells act on glycolipids to generate a highly simplified neoepitope composed of a sugar-free phosphate anion. Using knowledge of this processed antigen, we generated human CD1c tetramers, and demonstrate that CD1c-PM complexes stain T cell receptors (TCRs), providing direct evidence for a ternary interaction among CD1c-lipid-TCR. Furthermore, PM-loaded CD1c tetramers detect fresh human T cells from peripheral blood, demonstrating a polyclonal response to PM antigens in humans ex vivo.

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“…Numerous syntheses of R-TBSA have been reported, using chiral pool sources, 17,19,20 chiral auxiliaries, 21 catalytic enantioselective induction, 10,18 and resolution methods [14][15][16] (Table 1). The most efficient synthesis reported to date is that of Roberts and Baird who prepared TBSA in four steps from (S)-citronellyl bromide, in a route involving stepwise elongations using copper(I)-catalyzed cross-coupling and Wittig extension.…”

Section: Synthesis Of (R)-tuberculostearic Acidmentioning

confidence: 99%

“…Step 1 is catalyzed by phosphatidylglycerophosphate synthetase (PgsA3), which catalyzes the phosphatidylation of glycerol-3-phosphate by CDP-diacylglycerol to afford phosphatidylglycerophosphate; 7 and step 2 which involves the dephosphorylation of phosphatidylglycerophosphate to afford PG, by a phosphatidylglycerophosphatase. Mtb PG occurs as a range of lipoforms including an abundant species that bears (R)-tuberculostearic acid (R-TBSA) at the sn-1 position, and palmitic acid at the sn-2 position, 4 a decoration that matches that of other phosphatidyl-containing lipids 9 such as phosphatidylethanolamine, 10 and phosphatidylinositol mannosides. 11 Possibly because of its role as a biosynthetic intermediate, Mtb PG occurs at low levels and the challenges of its isolation 4 from the natural source are compounded by the pathogenicity and low growth rate of Mtb.…”

Section: Introductionmentioning

confidence: 99%

Total synthesis and mass spectrometric analysis of a Mycobacterium tuberculosis phosphatidylglycerol featuring a two-step synthesis of (R)-tuberculostearic acid

2017

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We report the total synthesis of (R)-tuberculostearic acid-containing Mycobacterium tuberculosis phosphatidylglycerol (PG). The approach features a two-step synthesis of (R)-tuberculostearic acid, involving an (S)-citronellyl bromide linchpin, and the phosphoramidite-assisted assembly of the full PG structure. Collision-induced dissociation mass spectrometry of two chemically-synthesized PG acyl regioisomers revealed diagnostic product ions formed by preferential loss of carboxylate at the secondary (sn-2) position.

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Asymmetric synthesis and structure elucidation of a glycerophospholipid from Mycobacterium tuberculosis

Cited by 21 publications

References 43 publications

Mycobacterium tuberculosis is extraordinarily sensitive to killing by a vitamin C-induced Fenton reaction

Mycobacterium tuberculosis is extraordinarily sensitive to killing by a vitamin C-induced Fenton reaction

CD1c tetramers detect ex vivo T cell responses to processed phosphomycoketide antigens

Total synthesis and mass spectrometric analysis of a Mycobacterium tuberculosis phosphatidylglycerol featuring a two-step synthesis of (R)-tuberculostearic acid

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