Structure of the Mycolic Acids of Mycobacteria

Asselineau, J.; Lederer, E.

doi:10.1038/166782a0

Cited by 90 publications

(54 citation statements)

References 9 publications

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“…We propose that the C 20 fatty acid is the starting point where the FAS-II systems take over for the synthesis of the very-long-chain mero segment of ␣-, methoxy-, and ketomycolic acids (see below). Meroacid is defined in this review as the long ␣-alkyl chain of mycolic acid that is released as a meroaldehyde by pyrolytic cleavage and is oxidized by a separate reaction to the fatty acid (8). FAS-I also produces hexacosanoyl-CoA (C 26 ), and this fatty acid becomes the short ␣-alkyl chain and methyl carboxyl segment of all mycolic acids of M. tuberculosis.…”

Section: Biosynthesis Of Normal Fatty Acid Precursors Of Mycolic Acidmentioning

confidence: 99%

Pathway to Synthesis and Processing of Mycolic Acids in Mycobacterium tuberculosis

2005

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Mycobacterium tuberculosis is known to synthesize α-, methoxy-, and keto-mycolic acids. We propose a detailed pathway to the biosynthesis of all mycolic acids in M. tuberculosis. Fatty acid synthetase I provides C20-S-coenzyme A to the fatty acid synthetase II system (FAS-IIA). Modules of FAS-IIA and FAS-IIB introduce cis unsaturation at two locations on a growing meroacid chain to yield three different forms of cis,cis-diunsaturated fatty acids (intermediates to α-, methoxy-, and keto-meroacids). These are methylated, and the mature meroacids and carboxylated C26-S-acyl carrier protein enter into the final Claisen-type condensation with polyketide synthase-13 (Pks13) to yield mycolyl-S-Pks13. We list candidate genes in the genome encoding the proposed dehydrase and isomerase in the FAS-IIA and FAS-IIB modules. We propose that the processing of mycolic acids begins by transfer of mycolic acids from mycolyl-S-Pks13 to d-mannopyranosyl-1-phosphoheptaprenol to yield 6-O-mycolyl-β-d-mannopyranosyl-1-phosphoheptaprenol and then to trehalose 6-phosphate to yield phosphorylated trehalose monomycolate (TMM-P). Phosphatase releases the phosphate group to yield TMM, which is immediately transported outside the cell by the ABC transporter. Antigen 85 then catalyzes the transfer of a mycolyl group from TMM to the cell wall arabinogalactan and to other TMMs to produce arabinogalactan-mycolate and trehalose dimycolate, respectively. We list candidate genes in the genome that encode the proposed mycolyltransferases I and II, phosphatase, and ABC transporter. The enzymes within this total pathway are targets for new drug discovery

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Section: Biosynthesis Of Normal Fatty Acid Precursors Of Mycolic Acidmentioning

confidence: 99%

Pathway to Synthesis and Processing of Mycolic Acids in Mycobacterium tuberculosis

2005

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“…Mycobacterial cultures at the mid-logarithmic growth phase were first mixed with [2][3][4][5][6][7][8][9][10][11][12][13][14] C]acetate (specific activity, 45 to 60 mCi mmol…”

Section: Total-protein Isolation and Western Blottingmentioning

confidence: 99%

“…Besides peptidoglycan surrounding the cytoplasmic membrane, this complex lipid-rich structure consists of an outer layer of mycolic acids covalently linked to arabinogalactan. Mycolic acids are long-chain (C ), high-molecular-weight ␤-hydroxy fatty acids with a short alkyl branch (C [24][25][26] ) in the ␣ position (2,9,17,39). The tightly packed layer of mycolate chains in the cell wall of Mycobacterium tuberculosis is responsible for its important characteristics, including resistance to chemical injury and dehydration, low permeability to hydrophobic antibiotics, and ability to form biofilms (19,23,24,52).…”

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confidence: 99%

AccD6, a Key Carboxyltransferase Essential for Mycolic Acid Synthesis in Mycobacterium tuberculosis, Is Dispensable in a Nonpathogenic Strain

et al. 2011

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Acetyl coenzyme A carboxylase (ACC) is a key enzyme providing a substrate for mycolic acid biosynthesis. Although in vitro studies have demonstrated that the protein encoded by accD6 (Rv2247) may be a functional carboxyltransferase subunit of ACC in Mycobacterium tuberculosis, the in vivo function and regulation of accD6 in slow-and fast-growing mycobacteria remain elusive. Here, directed mutagenesis demonstrated that although accD6 is essential for M. tuberculosis, it can be deleted in Mycobacterium smegmatis without affecting its cell envelope integrity. Moreover, we showed that although it is part of the type II fatty acid synthase operon, the accD6 gene of M. tuberculosis, but not that of M. smegmatis, possesses its own additional promoter (P acc ). The expression level of accD6 Mtb placed only under the control of P acc is 10-fold lower than that in wild-type M. tuberculosis but is sufficient to sustain cell viability. Importantly, this limited expression level affects growth, mycolic acid content, and cell morphology. These results provide the first in vivo evidence for AccD6 as a key player in the mycolate biosynthesis of M. tuberculosis, implicating AccD6 as the essential ACC subunit in pathogenic mycobacteria and an excellent target for new antitubercular compounds. Our findings also highlight important differences in the mechanism of acetyl carboxylation between pathogenic and nonpathogenic mycobacterial species.

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“…Mycolic acids are very long-chain (up to C90) ␣-branched, ␤-hydroxylated fatty acids, specific to mycobacteria and related genera (Minnikin, 1982;Asselineau and Lederer, 1950). These major cell-wall components (40-60% of the cell dry weight) are believed to play an essential role in the architecture of the mycobacterial cell envelope .…”

Section: Introductionmentioning

confidence: 99%

Mycobacteriumbovis BCG genes involved in the biosynthesis of cyclopropyl keto‐ and hydroxy‐mycolic acids

Dubnau¹,

Lanéelle

Soares³

et al. 1997

Molecular Microbiology

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SummaryThe resurgence of tuberculosis and the emergence of multidrug-resistant mycobacteria necessitate the development of new antituberculosis drugs. The biosynthesis of mycolic acids, essential elements of the mycobacterial envelope, is a good target for chemotherapy. Species of the Mycobacterium tuberculosis complex synthesize oxygenated mycolic acids with keto and methoxy functions. In contrast, the fastgrowing Mycobacterium smegmatis synthesizes oxygenated mycolic acids with an epoxy function. We describe the isolation and sequencing of a cluster of four genes from Mycobacterium bovis bacillus Calmette-Gué rin (BCG), coding for methyl transferases, and which, when transferred into M. smegmatis, allow the synthesis of ketomycolic acid, in addition to an as yet undescribed mycolic acid, hydroxymycolic acid. These oxygenated mycolic acids, unlike the regular mycolic acids of M. smegmatis, and similar to the mycolic acids of M. bovis, are highly cyclopropanated. Furthermore, there is a perfect match between the structures of the keto-and the hydroxy-mycolic acids. We propose a biosynthetic model in which there is a direct relationship between these two types of mycolic acid.

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Structure of the Mycolic Acids of Mycobacteria

Cited by 90 publications

References 9 publications

Pathway to Synthesis and Processing of Mycolic Acids in Mycobacterium tuberculosis

Pathway to Synthesis and Processing of Mycolic Acids in Mycobacterium tuberculosis

AccD6, a Key Carboxyltransferase Essential for Mycolic Acid Synthesis in Mycobacterium tuberculosis, Is Dispensable in a Nonpathogenic Strain

Mycobacteriumbovis BCG genes involved in the biosynthesis of cyclopropyl keto‐ and hydroxy‐mycolic acids

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