Structural elucidation of new phenolic glycolipids from Mycobaclerium tuberculosis

Watanabe, Motoko; Yamada, Yasuji; Iguchi, Kazuo; Minnikin, David E.

doi:10.1016/0005-2760(94)90118-x

Cited by 21 publications

(12 citation statements)

References 25 publications

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“…Evidence for the Production of p-Hydroxybenzoate Derivatives by M. tuberculosis-All strains of M. tuberculosis examined to date synthesize DIMs (41, 7), but only few of them produce the structurally related PGLs (24,25,42,43). However many sera from tuberculous patients in diverse geographic regions contain antibodies specifically recognizing the major PGL of the Canetti subspecies (PGL-tb) (11)(12)(13).…”

Section: Resultsmentioning

confidence: 99%

Role of the pks15/1 Gene in the Biosynthesis of Phenolglycolipids in the Mycobacterium tuberculosisComplex

Constant¹,

Pérez²,

Malaga

et al. 2002

Journal of Biological Chemistry

227

181

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Diesters of phthiocerol and phenolphthiocerol are important virulence factors of Mycobacterium tuberculosis and Mycobacterium leprae, the two main mycobacterial pathogens in humans. They are both long-chain ␤-diols, and their biosynthetic pathway is beginning to be elucidated. Although the two classes of molecules share a common lipid core, phthiocerol diesters have been found in all the strains of the M. tuberculosis complex examined although phenolphthiocerol diesters are produced by only a few groups of strains. To address the question of the origin of this diversity 8 reference strains and 10 clinical isolates of M. tuberculosis were analyzed. We report the presence of glycosylated p-hydroxybenzoic acid methyl esters, structurally related to the type-specific phenolphthiocerol glycolipids, in the culture media of all reference strains of M. tuberculosis, suggesting that the strains devoid of phenolphthiocerol derivatives are unable to elongate the putative p-hydroxybenzoic acid precursor. We also show that all the strains of M. tuberculosis examined and deficient in the production of phenolphthiocerol derivatives are natural mutants with a frameshift mutation in pks15/1 whereas a single open reading frame for pks15/1 is found in Mycobacterium bovis BCG, M. leprae, and strains of M. tuberculosis that produce phenolphthiocerol derivatives. Complementation of the H37Rv strain of M. tuberculosis, which is devoid of phenolphthiocerol derivatives, with the fused pks15/1 gene from M. bovis BCG restored phenolphthiocerol glycolipids production. Conversely, disruption of the pks15/1 gene in M. bovis BCG led to the abolition of the synthesis of type-specific phenolphthiocerol glycolipid. These data indicate that Pks15/1 is involved in the elongation of p-hydroxybenzoic acid to give p-hydroxyphenylalkanoates, which in turn are converted, presumably by the PpsA-E synthase, to phenolphthiocerol derivatives.

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Section: Resultsmentioning

confidence: 99%

Role of the pks15/1 Gene in the Biosynthesis of Phenolglycolipids in the Mycobacterium tuberculosisComplex

Constant¹,

Pérez²,

Malaga

et al. 2002

Journal of Biological Chemistry

227

181

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“…Table 1. Of the M. tuberculosis strains, O and K were newly separated clinical isolates, subcultured on egg slants only three times before the present culture in Kirchner's medium (Watanabe et al, 1994). Aoyama B is a Japanese standard strain used for the preparation of PPD.…”

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confidence: 99%

“…For preparative TLC, Merck 5744 plates were used, with a 2 % ethanolic spray solution of Rhodamine 6G for detection under UV light. (Watanabe et al, 1994). Aoyama B is a Japanese standard strain used for the preparation of PPD.…”

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confidence: 99%

Separation and characterization of individual mycolic acids in representative mycobacteria

et al. 2001

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Total mycolic acid methyl ester fractions were isolated from 24 representatives of Mycobacterium tuberculosis, Mycobacterium bovis (including BCG), Mycobacterium microti, Mycobacterium kansasii and Mycobacterium avium. The total mycolate functional group composition was estimated from 1 H-NMR spectra. Mycolates were separated into α-mycolates, methoxymycolates and ketomycolates and each class was further separated by argentation chromatography into mycolates with no double bonds, with one trans-double bond and with one cis-double bond. Mass spectrometry revealed the mycolate chain lengths and 1 H-NMR the cis-and trans-double bond and cyclopropane ring content. The same species had similar mycolate profiles ; the major type of each class had cis-or trans-cyclopropane rings and lacked double bonds. Minor proportions of possible unsaturated precursors of the cyclopropane mycolates were commonly encountered. Among unusual α-mycolates, many strains had tricyclopropyl components with chains extended by 6 to 8 carbons.Significantly, M. tuberculosis (Canetti) and M. avium had α-mycolates with a trans-double bond and cyclopropane ring, whose chain lengths suggested a relationship to possible precursors of oxygenated mycolates. The methoxyand ketomycolates from a majority of M. tuberculosis strains had minor amounts of components with additional cyclopropane rings, some of whose chains were also extended by 6 to 8 carbons. These latter mycolates were major components in the attenuated M. tuberculosis H37Ra strain, whose mycolate profile was distinct from those of other strains of M. tuberculosis.Keywords : mycobacterial mycolates, cyclopropane rings, double bonds, stereochemistry, tuberculosis INTRODUCTIONMycobacterial mycolic acids, whose general structures are indicated in Fig. 1, are high-molecular-mass 2-alkyl branched, 3-hydroxy fatty acids, which are characteristic components of the cell envelope of mycobacteria.Although they are present in the extractable lipids, mostly as trehalose dimycolates, the major portion is covalently bound in the cell envelope esterified to the 5-hydroxy groups of arabinofuranosyl residues to form the terminal [5-mycoloyl-β-Araf-(1 2)-5-mycoloyl-α-Araf-(1 )] units of a major arabinogalactan polysaccharide (McNeil et al., 1991 galactan is, in turn, attached to the shape-forming peptidoglycan. Schematic models of mycobacterial envelope structure have been proposed to show possible arrangements for the mycolic acids and other lipid components (McNeil & Brennan, 1991 ;Minnikin, 1991 ;Paul & Beveridge, 1994). According to the currently accepted structural model (Brennan & Nikaido, 1995 ;Daffe! & Draper, 1998 ;Draper, 1998), the long hydrocarbon chains of the mycolic acids are arranged in an orderly fashion, in parallel, with the methyl ends towards the outside surface. This arrangement results in the electrontransparent layer of the cell envelope, the presence of which is revealed by electron micrographs of ultra-thin sections of mycobacterial cells (Paul & Beveridge, 1992 in the major ' merom...

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“…Moreover, breakdown of mycolates results in liberation of the free gaseous form of cyclopropane, which was present in 1 H NMR spectra of cerebrospinal fluid samples from patients with tuberculous meningitis (48). Mycobacterium species are known to possess various forms of phenolic glycolipids as integral membrane structural components (49,50), and may have a role in the inhibition of phagocytosis by macrophages (51). Tissue destruction during TB infection often leads to cheese-like formation of necrotic tissue (caseation) caused by membrane rupture of MTB during phagocytosis, which is unique to tuberculomas.…”

Section: Discussionmentioning

confidence: 99%

NMR spectroscopic identification of cholesterol esters, plasmalogen and phenolic glycolipids as fingerprint markers of human intracranial tuberculomas

et al. 2007

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Detailed (1)H and (13)C NMR spectroscopy of lipid extracts from 12 human intracranial tuberculomas and two control brain tissue samples was performed to assess the role of lipids in the disease process. One-dimensional and two-dimensional NMR techniques were used to resolve the mixture of lipid components and make resonance assignments. The lipid components that could be identified in tuberculoma lipid extracts and not in control samples were: cholesterol ester, plasmalogen and phenolic glycolipids. It is proposed that the combined occurrence of these lipid components can be used as 'fingerprint markers' for the differentiation of intracranial tuberculoma from healthy brain tissue. Furthermore, phenolic glycolipids present in intracranial tuberculomas may have diagnostic significance in differentiating them from other disease conditions of the central nervous system such as malignant tumors.

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Structural elucidation of new phenolic glycolipids from Mycobaclerium tuberculosis

Cited by 21 publications

References 25 publications

Role of the pks15/1 Gene in the Biosynthesis of Phenolglycolipids in the Mycobacterium tuberculosisComplex

Role of the pks15/1 Gene in the Biosynthesis of Phenolglycolipids in the Mycobacterium tuberculosisComplex

Separation and characterization of individual mycolic acids in representative mycobacteria

NMR spectroscopic identification of cholesterol esters, plasmalogen and phenolic glycolipids as fingerprint markers of human intracranial tuberculomas

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