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Chapter 19 : A Waxy Tale, by Mycobacterium tuberculosis

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Abstract:

The cell envelope differs substantially from the canonical cell wall structures of both gram-negative and gram-positive bacteria. This chapter reviews the current understanding of the major cell wall waxes found in , along with their functions and biosynthesis. Mycolic acids have unique characteristics essential for maintaining the cell wall structure, and their physiological role may possibly be correlated to individual mycolates. The major biological functions associated with mycolic acid either bound to arabinogalactan (AG) or associated with trehalose are summarized. The phthiocerol dimycoserosates (PDIMs) are major waxes of the tubercle bacillus. Two types of fatty acid-synthesizing systems, fatty acid synthase I (FAS-I) and fatty acid synthase II (FAS-II), achieve the enzymatic cycles. Through genetic and biochemical approaches, two genes of the FAS-II system, and , have been postulated to encode the primary target of isoniazid (INH). Therefore, due to conflicting reports, the mode of action of INH has recently been reexamined. First, studies performed in vivo demonstrated that overexpression of InhA, but not KasA, in , BCG, and conferred increased resistance to INH. Second, in vitro assays using purified KasA or InhA demonstrated that KatG-activated INH inhibited InhA activity but not KasA activity. A recent review of mycolic acid biosynthesis discusses the possibility that mycobacteria may use more than one pathway for the biosynthesis of mycolates.

Citation: Kremer L, Besra G. 2005. A Waxy Tale, by Mycobacterium tuberculosis, p 287-305. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch19

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Figures

Image of Figure 1.
Figure 1.

Simplified representation of the mycobacterial cell wall from . Adapted from references 41 and 76. © 2002 with permission from Elsevier.

Citation: Kremer L, Besra G. 2005. A Waxy Tale, by Mycobacterium tuberculosis, p 287-305. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch19
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Image of Figure 2.
Figure 2.

αMycolate from .

Citation: Kremer L, Besra G. 2005. A Waxy Tale, by Mycobacterium tuberculosis, p 287-305. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch19
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Image of Figure 3.
Figure 3.

Mycobacterial α-mycolates and oxygenated mycolates. , trans; , cis.

Citation: Kremer L, Besra G. 2005. A Waxy Tale, by Mycobacterium tuberculosis, p 287-305. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch19
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Image of Figure 4.
Figure 4.

Tetramycolyl hexaarabinoside unit of mAGP.

Citation: Kremer L, Besra G. 2005. A Waxy Tale, by Mycobacterium tuberculosis, p 287-305. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch19
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Image of Figure 5.
Figure 5.

Representative structures of glucose monomycolate (GMM), trehalose dimycolate (TDM), and 6--mycolyl-ß-Dmannopyranosyl monophosphooctahydroheptaprenol (MycPL).

Citation: Kremer L, Besra G. 2005. A Waxy Tale, by Mycobacterium tuberculosis, p 287-305. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch19
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Image of Figure 6.
Figure 6.

Major functions assigned to mycolic acids bound to AG or to TDM.

Citation: Kremer L, Besra G. 2005. A Waxy Tale, by Mycobacterium tuberculosis, p 287-305. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch19
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Image of Figure 7.
Figure 7.

Representation of some complex lipids in . Adapted from reference 76. © 2002 with permission from Elsevier.

Citation: Kremer L, Besra G. 2005. A Waxy Tale, by Mycobacterium tuberculosis, p 287-305. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch19
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Image of Figure 8.
Figure 8.

Representation of PDIM as well as PGLs from BCG (also called mycoside B) and from the Canetti strain of .

Citation: Kremer L, Besra G. 2005. A Waxy Tale, by Mycobacterium tuberculosis, p 287-305. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch19
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Image of Figure 9.
Figure 9.

Representation of the structural relationship between LM, LAM, and PIM. Adapted from reference 62 with permission from the publisher.

Citation: Kremer L, Besra G. 2005. A Waxy Tale, by Mycobacterium tuberculosis, p 287-305. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch19
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Image of Figure 10.
Figure 10.

Biosynthesis of α-mycolic acids in .

Citation: Kremer L, Besra G. 2005. A Waxy Tale, by Mycobacterium tuberculosis, p 287-305. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch19
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Image of Figure 11.
Figure 11.

FAS-I and FAS-II systems in . Inhibition of the FAS-II enzymes InhA and KasA by various antitubercular agents is shown by an arrow. TLM, thiolactomycin; ETH, ethionamide; TRC, triclosan.

Citation: Kremer L, Besra G. 2005. A Waxy Tale, by Mycobacterium tuberculosis, p 287-305. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch19
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Image of Figure 12.
Figure 12.

Three-step mechanism of the Claisen-type condensation reaction. R′, CoA, specific for mtFabH; R′, AcpM, specific for KasA/KasB.

Citation: Kremer L, Besra G. 2005. A Waxy Tale, by Mycobacterium tuberculosis, p 287-305. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch19
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Image of Figure 13.
Figure 13.

Proposed pathway for the biosynthesis of the PIMs, linear LM, native LM, and LAM of mycobacteria. Adapted from references 65 and 80 with permission from the publishers.

Citation: Kremer L, Besra G. 2005. A Waxy Tale, by Mycobacterium tuberculosis, p 287-305. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch19
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