Lipid Phenotype of Two Distinct Subpopulations of Mycobacterium bovis Bacillus Calmette-Guérin Tokyo 172 Substrain

Naka, Takashi; Maeda, Shingo; Niki, Mamiko; Ohara, Naoya; Yamamoto, Saburo; Yano, Ikuya; Maeyama, Jun ichi; Ogura, Hisashi; Kobayashi, Kazuo; Fujiwara, Nagatoshi

doi:10.1074/jbc.m111.310037

Cited by 25 publications

(23 citation statements)

References 36 publications

(46 reference statements)

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“…The observed [DIM A ϩ Na] ϩ ion, with an m/z value of 1,348.738 (Fig. 4, left panel), represents a molecule with 89 carbon atoms (C 89 species; theoretical mass, 1,348.3409) that has been reported for the highest-intensity peak in the mass spectrum for a DIM A preparation from M. bovis BCG strain Tokyo 172 (13,54). The m/z values for other ions were higher or lower than that for the C 89 species, by n ϫ 14 units (Fig.…”

Section: Analysis Of the Structural Characteristics Of The Rv2951c Prmentioning

confidence: 99%

F ₄₂₀ H ₂ Is Required for Phthiocerol Dimycocerosate Synthesis in Mycobacteria

Purwantini

Daniels²,

Mukhopadhyay

2016

J Bacteriol

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Phthiocerol dimycocerosates (PDIM) are a group of cell surface-associated apolar lipids of Mycobacterium tuberculosis and closely related mycobacteria, such as Mycobacterium bovis and Mycobacterium leprae. A characteristic methoxy group of these lipids is generated from the methylation of a hydroxyl group of the direct precursors, the phthiotriols. The precursors arise from the reduction of phthiodiolones, the keto intermediates, by a ketoreductase. The putative phthiodiolone ketoreductase (PKR) is encoded by Rv2951c in M. tuberculosis and BCG_2972c in M. bovis BCG, and these open reading frames (ORFs) encode identical amino acid sequences. We investigated the cofactor requirement of the BCG_2972c protein. A comparative analysis based on the crystallographic structures of similar enzymes identified structural elements for binding of coenzyme F 420 and hydrophobic phthiodiolones in PKR. Coenzyme F 420 is a deazaflavin coenzyme that serves several key functions in pathogenic and nonpathogenic mycobacteria. We found that an M. bovis BCG mutant lacking F 420 -dependent glucose-6-phosphate dehydrogenase (Fgd), which generates F 420 H 2 (glucose-6-phosphate ؉ F 420 ¡ 6-phosphogluconate ؉ F 420 H 2 ), was devoid of phthiocerols and accumulated phthiodiolones. When the mutant was provided with F 420 H 2 , a broken-cell slurry of the mutant converted accumulated phthiodiolones to phthiocerols; F 420 H 2 was generated in situ from F 420 and glucose-6-phosphate by the action of Fgd. Thus, the reaction mixture was competent in reducing phthiodiolones to phthiotriols (phthiodiolones ؉ F 420 H 2 ¡ phthiotriols ؉ F 420 ), which were then methylated to phthiocerols. These results established the mycobacterial phthiodiolone ketoreductase as an F 420 H 2 -dependent enzyme (fPKR). A phylogenetic analysis of close homologs of fPKR revealed potential F 420 -dependent lipidmodifying enzymes in a broad range of mycobacteria. IMPORTANCEMycobacterium tuberculosis is the causative agent of tuberculosis, and phthiocerol dimycocerosates (PDIM) protect this pathogen from the early innate immune response of an infected host. Thus, the PDIM synthesis system is a potential target for the development of effective treatments for tuberculosis. The current study shows that a PDIM synthesis enzyme is dependent on the coenzyme F 420 . F 420 is universally present in mycobacteria and absent in humans. This finding expands the number of experimentally validated F 420 -dependent enzymes in M. tuberculosis to six, each of which helps the pathogen to evade killing by the host immune system, and one of which activates an antituberculosis drug, PA-824. This work also has relevance to leprosy, since similar waxy lipids are found in Mycobacterium leprae.

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Section: Analysis Of the Structural Characteristics Of The Rv2951c Prmentioning

confidence: 99%

F ₄₂₀ H ₂ Is Required for Phthiocerol Dimycocerosate Synthesis in Mycobacteria

Purwantini

Daniels²,

Mukhopadhyay

2016

J Bacteriol

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“…ese results for the major MA subclasses agreed with the results obtained by using TLC and MALDI-TOFMS. 25,26,32) A wealth of information on MALDI mass spectra exists; however, valuable information corresponding to all the MAs in each sample was, until now, unable to be viewed at a glance. We made contour maps for the normalized relative peak intensities of all MAs so as to visualize the MA subclasses and their distribution of carbon-chain lengths (Figs.…”

Section: Analysis Of Ma Subclasses In Tlc Fractionsmentioning

confidence: 99%

“…In the many cases, MALDI-TOFMS has been used to con rm the molecular species and the distribution of MAs in TLC fractions. 24,25) ese information were reported in the papers where proposal of the new species. 26) However the sample preparation of MALDI-TOFMS is easy and mass-resolution is relatively high, extraction of puri ed subclass MA MEs from TLC plate was cumbersome.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Mycolic Acids in Total Fatty Acid Methyl Ester Fractions from <i>Mycobacterium</i> Species by High Resolution MALDI-TOFMS

et al. 2015

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Mycolic acids (MAs) are characteristic components of bacteria in the suborder Corynebacterineae, such as Mycobacterium. MAs are categorized into subclasses based on their functional bases (cyclopropane ring, methoxy, keto, and epoxy group). Since MAs have heterogeneity among bacterial species, analyzing of MAs are required in the chemotaxonomic eld. However, their structural analysis is not easy because of their long carbon-chain lengths and several functional groups. In this study, total fatty acid (FA) methyl ester (ME) fraction of M. tuberculosis H37Rv was analyzed by matrix-assisted laser desorption/ionization (MALDI) time-of-ight mass spectrometry (TOFMS) with a spiral ion trajectory (MALDI spiral-TOFMS).e distributions of carbon-chain length and their relative peak intensities were con rmed with those obtained by analysis of each subclass fraction which was separated from total FA ME fraction using thin-layer chromatography (TLC). e observed major peaks were reliably assigned as MAs owing to the high mass accuracy (error<3 ppm). e types of MA subclasses, their distributions of carbon-chain lengths, their relative peak intensities, and the ratio of even-and odd-numbered carbon-chain MAs for the total FA ME fraction were consistent with those of MA subclass fractions. To visualize whole MAs, contour maps of relative peak intensities for whole MAs were created. e contour maps indicated the MA subclasses and their distributions of carbon-chains with relative peak intensities at a glance. Our proposed method allows simple characterization in a short time and thus enables the analysis of large numbers of samples, and it would contribute to the chemotaxonomy.Please cite this article as: Mass Spectrom (Tokyo) 2015; 4(1): A0035

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“…The binding affinity of three strains of BCG (TICE, Connaught and Frappier strains, which are closely related genetically) to fibronectin in vitro appeared to be equivalent. 36 The prior report of Chen et al 35 whether the BCG Japan they used was the same as the BCG Tokyo 172 strain used in the above-cited in vitro antitumor study. 34 That study also showed that BCG Japan, BCG Moreau and BCG Glaxo do not produce phthiocerol dimycocerosates (PDIM) or phenolic glycolipids (PGL) (cell wall components known to be important for bacterial virulence) ( 35 It was suggested that Rv3405c encodes a transcription factor of the TetR family, and is responsible for the biosynthesis of PDIM/PGL in the BCG Japan and Moreau strains, but not in BCG Glaxo.…”

Section: Genetic Differences and The Different Immune Responses Of Bcmentioning

confidence: 99%

Bacillus Calmette–Guérin strain differences as the basis for immunotherapies against bladder cancer

et al. 2018

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In the past 40 years, intravesical immunotherapy with Mycobacterium bovis bacillus Calmette-Guérin has been carried out as the most effective treatment for preventing local recurrences and tumor progression of non-muscle-invasive bladder cancer. Bacillus Calmette-Guérin is a family of vaccines derived in 1921 by the in vitro attenuation of Mycobacterium bovis. Subsequently, bacillus Calmette-Guérin seed lots were spread around the world, and both phenotypic and genotypic differences among the strains have been compiled. In recent genomic comparisons, the evolution of the different bacillus Calmette-Guérin substrains has begun to emerge. However, some of these genetic alterations in bacillus Calmette-Guérin strains have yet to be shown to affect the therapeutic effects and/or adverse effects. There are thus ongoing research efforts to assess the effects of these genetic alterations on the properties of bacillus Calmette-Guérin strains, with the ultimate goal of identifying an ideal bacillus Calmette-Guérin strain for treatment of non-muscle-invasive bladder cancer and providing clues for the improvement of bacillus Calmette-Guérin strains. The present review provides a history of bacillus Calmette-Guérin immunotherapy, and discusses the genetic differences among bacillus Calmette-Guérin strains, the different clinical outcomes afforded by bacillus Calmette-Guérin strains and possible future developments.

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Lipid Phenotype of Two Distinct Subpopulations of Mycobacterium bovis Bacillus Calmette-Guérin Tokyo 172 Substrain

Cited by 25 publications

References 36 publications

F ₄₂₀ H ₂ Is Required for Phthiocerol Dimycocerosate Synthesis in Mycobacteria

F ₄₂₀ H ₂ Is Required for Phthiocerol Dimycocerosate Synthesis in Mycobacteria

Characterization of Mycolic Acids in Total Fatty Acid Methyl Ester Fractions from <i>Mycobacterium</i> Species by High Resolution MALDI-TOFMS

Bacillus Calmette–Guérin strain differences as the basis for immunotherapies against bladder cancer

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Lipid Phenotype of Two Distinct Subpopulations of Mycobacterium bovis Bacillus Calmette-Guérin Tokyo 172 Substrain

Cited by 25 publications

References 36 publications

F 420 H 2 Is Required for Phthiocerol Dimycocerosate Synthesis in Mycobacteria

F 420 H 2 Is Required for Phthiocerol Dimycocerosate Synthesis in Mycobacteria

Characterization of Mycolic Acids in Total Fatty Acid Methyl Ester Fractions from <i>Mycobacterium</i> Species by High Resolution MALDI-TOFMS

Bacillus Calmette–Guérin strain differences as the basis for immunotherapies against bladder cancer

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F ₄₂₀ H ₂ Is Required for Phthiocerol Dimycocerosate Synthesis in Mycobacteria

F ₄₂₀ H ₂ Is Required for Phthiocerol Dimycocerosate Synthesis in Mycobacteria