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4 A Comprehensive Overview of Mycolic Acid Structure and Biosynthesis

Authors: Hedia Marrakchi1, Fabienne Bardou2, Marie-antoinette Lanéelle3, Mamadou Daffé4
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Affiliations: 1: Department of Molecular Mechanisms of Mycobacterial Infections, Institut de Pharmacologie et de Biologie Structurale du Centre National de la Recherche Scientifique (CNRS), and Université Paul Sabatier, 205 route de Narbonne, 31077 Toulouse Cedex 4, France; 2: Department of Molecular Mechanisms of Mycobacterial Infections, Institut de Pharmacologie et de Biologie Structurale du Centre National de la Recherche Scientifique (CNRS), and Université Paul Sabatier, 205 route de Narbonne, 31077 Toulouse Cedex 4, France; 3: Department of Molecular Mechanisms of Mycobacterial Infections, Institut de Pharmacologie et de Biologie Structurale du Centre National de la Recherche Scientifique (CNRS), and Université Paul Sabatier, 205 route de Narbonne, 31077 Toulouse Cedex 4, France; 4: Department of Molecular Mechanisms of Mycobacterial Infections, Institut de Pharmacologie et de Biologie Structurale du Centre National de la Recherche Scientifique (CNRS), and Université Paul Sabatier, 205 route de Narbonne, 31077 Toulouse Cedex 4, France
Content Type: Monograph
Publication Year: 2008
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Abstract:

This chapter focuses on the major metabolic steps and essential enzymatic players in the mycolic acid biosynthetic pathway, providing a historical perspective and highlighting the key advances of the last few years in this dynamic area. Information relative to the mycolic acid structure has been brought through the application of early and modern chemical techniques, in particular thin-layer chromatography (TLC), gas chromatography (GC), high-pressure liquid chromatography, mass spectrometry, and nuclear magnetic resonance spectroscopy. The structures of mycolic acids of genera other than mycobacteria were found to be relatively simple in terms of chemical functions, being composed only of homologous series with various numbers of double bonds, up to 7 for some species. The pathway for synthesis of mycolic acids could be virtually divided into three major steps: (1) the synthesis and elongation of fatty acids to give precursors of both the α-branch and the very long meromycolic chain; (2) the elongation and introduction of functional modifications on the meromycolic chain; and (3) the condensation of two long-chain fatty acids, followed by a reduction to yield the mycolic acid specific motif. More recently, the involvement of the AccD4 carboxyltransferase in mycolic acid synthesis and its essentiality for mycobacterial survival have been demonstrated. Fatty acid synthase (FAS)-II has been shown to elongate medium-chain-length to C fatty acids to yield C-C acyl-ACPs in vitro, which are most likely the precursors of the very long-chain meromycolic acids.

Citation: Marrakchi H, Bardou F, Lanéelle M, Daffé M. 2008. 4 A Comprehensive Overview of Mycolic Acid Structure and Biosynthesis, p 41-61. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch4

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4 A Comprehensive Overview of Mycolic Acid Structure and Biosynthesis
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Citation: Marrakchi H, Bardou F, Lanéelle M, Daffé M. 2008. 4 A Comprehensive Overview of Mycolic Acid Structure and Biosynthesis, p 41-61. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch4
/content/10.1128/9781555815783.ch04.ch04fig01
Figure 1.
Chemical features of the mycolic acid structure. (A) Scheme of the pyrolytical cleavage of mycolic acid. R and R′ represent long hydrocarbon chains. (B) The C corynomycolic acid: 2-tetradecyl, 3-hydroxy octadecanoic acid from , where indicates the stereochemistry of carbons 2 and 3. The pyrolysis releases C acid and C “meroaldehyde.” (C) The dicyclopropanated mycolic acid (α-mycolate) from : the pyrolysis of the C homologue releases C acid and C “meroaldehyde.”
10.1128/9781555815783/f0042-01_thmb.gif
10.1128/9781555815783/f0042-01.gif
Image of Figure 1.
Figure 1.

Chemical features of the mycolic acid structure. (A) Scheme of the pyrolytical cleavage of mycolic acid. R and R′ represent long hydrocarbon chains. (B) The C corynomycolic acid: 2-tetradecyl, 3-hydroxy octadecanoic acid from , where indicates the stereochemistry of carbons 2 and 3. The pyrolysis releases C acid and C “meroaldehyde.” (C) The dicyclopropanated mycolic acid (α-mycolate) from : the pyrolysis of the C homologue releases C acid and C “meroaldehyde.”

Citation: Marrakchi H, Bardou F, Lanéelle M, Daffé M. 2008. 4 A Comprehensive Overview of Mycolic Acid Structure and Biosynthesis, p 41-61. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch4
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/content/10.1128/9781555815783.ch04.ch04fig02
Figure 2.
Structures of representative types of mycolic acids and established/proposed functions of mycolic acid SAM-methyltransferases (MA-MTs)., representative species where these mycolate types occur are shown. The mycolate types displayed illustrate the functional groups of interest and therefore may not reflect the most abundant mycolate components. The indicate the configuration of unsaturations (double bonds or cyclopropanes) at the distal/proximal position. and , when known, refer to the stereochemistry of the asymmetric centers (i.e., carbons bearing the methyl, methoxyl or hydroxyl groups). Arrows point to the known or predicted action of the mycolic acid SAM-methyltransferases (MA-MTs) whose functions have been assigned by gene knockout or by heterologous expression (into parentheses).
10.1128/9781555815783/f0043-01_thmb.gif
10.1128/9781555815783/f0043-01.gif
Image of Figure 2.
Figure 2.

Structures of representative types of mycolic acids and established/proposed functions of mycolic acid SAM-methyltransferases (MA-MTs)., representative species where these mycolate types occur are shown. The mycolate types displayed illustrate the functional groups of interest and therefore may not reflect the most abundant mycolate components. The indicate the configuration of unsaturations (double bonds or cyclopropanes) at the distal/proximal position. and , when known, refer to the stereochemistry of the asymmetric centers (i.e., carbons bearing the methyl, methoxyl or hydroxyl groups). Arrows point to the known or predicted action of the mycolic acid SAM-methyltransferases (MA-MTs) whose functions have been assigned by gene knockout or by heterologous expression (into parentheses).

Citation: Marrakchi H, Bardou F, Lanéelle M, Daffé M. 2008. 4 A Comprehensive Overview of Mycolic Acid Structure and Biosynthesis, p 41-61. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch4
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Figure 3.
Model of the mycolic acid biosynthetic pathway in mycobacteria. The biosynthesis pathway of mycolic acids starts with the de novo synthesis and elongation of fatty acids operated by the mycobacterial FAS-I and FAS-II synthases, respectively. The FAS-II products have to undergo further elongation and modifications/decorations to produce the very long “meromycolic” chain precursors, whereas the carboxylation of acyl-CoAs (the FAS-I products) provides the activated alpha branch. Condensation of the latter with the activated “meromycolic” chain, followed by reduction, yields the mycolic acid with the characteristic motif.
10.1128/9781555815783/f0045-01_thmb.gif
10.1128/9781555815783/f0045-01.gif
Image of Figure 3.
Figure 3.

Model of the mycolic acid biosynthetic pathway in mycobacteria. The biosynthesis pathway of mycolic acids starts with the de novo synthesis and elongation of fatty acids operated by the mycobacterial FAS-I and FAS-II synthases, respectively. The FAS-II products have to undergo further elongation and modifications/decorations to produce the very long “meromycolic” chain precursors, whereas the carboxylation of acyl-CoAs (the FAS-I products) provides the activated alpha branch. Condensation of the latter with the activated “meromycolic” chain, followed by reduction, yields the mycolic acid with the characteristic motif.

Citation: Marrakchi H, Bardou F, Lanéelle M, Daffé M. 2008. 4 A Comprehensive Overview of Mycolic Acid Structure and Biosynthesis, p 41-61. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch4
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Figure 4.
Mycobacterial (FAS-II) fatty acid synthesis. The names of the FAS-II orthologue proteins are indicated into parentheses. The malonyl-CoA:ACP transacylase (MtFabD) converts malonyl-CoA into malonyl-ACP. Cycles of fatty acid elongation are initiated by the condensation of acyl-CoAs (products of FAS-I) with malonyl-ACP catalyzed by β-ketoacyl-ACP synthase III (MtFabH). The second step in the elongation cycle is carried out by the β-ketoacyl-ACP reductase, MabA. The β-hydroxyacyl-ACP intermediate is dehydrated to form -2-enoyl-ACP. The final step in the elongation is catalyzed by the nicotinamide adenine dinucleotide (NADH)-dependent enoyl-ACP reductase (InhA). Subsequent rounds of elongation are initiated by the elongation condensing enzymes (KasA and KasB) whose substrate specificities govern the structure and distribution of fatty acid products.
10.1128/9781555815783/f0048-01_thmb.gif
10.1128/9781555815783/f0048-01.gif
Image of Figure 4.
Figure 4.

Mycobacterial (FAS-II) fatty acid synthesis. The names of the FAS-II orthologue proteins are indicated into parentheses. The malonyl-CoA:ACP transacylase (MtFabD) converts malonyl-CoA into malonyl-ACP. Cycles of fatty acid elongation are initiated by the condensation of acyl-CoAs (products of FAS-I) with malonyl-ACP catalyzed by β-ketoacyl-ACP synthase III (MtFabH). The second step in the elongation cycle is carried out by the β-ketoacyl-ACP reductase, MabA. The β-hydroxyacyl-ACP intermediate is dehydrated to form -2-enoyl-ACP. The final step in the elongation is catalyzed by the nicotinamide adenine dinucleotide (NADH)-dependent enoyl-ACP reductase (InhA). Subsequent rounds of elongation are initiated by the elongation condensing enzymes (KasA and KasB) whose substrate specificities govern the structure and distribution of fatty acid products.

Citation: Marrakchi H, Bardou F, Lanéelle M, Daffé M. 2008. 4 A Comprehensive Overview of Mycolic Acid Structure and Biosynthesis, p 41-61. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch4
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Figure 5.
Model of the mycolic acid condensation. R1 and R2 represent long hydrocarbon chains, and X1 and X2 are the unknown intermediate acceptors. The fatty acid molecule bearing R1 is activated as acyl-adenylate (acyl-AMP) by FadD32 to yield the “meromycolate” chain. The other condensation substrate containing the R2 chain is activated by the acyl-CoA carboxylase complex to give the carboxylated intermediate at the origin of the α-branch. Condensation is catalyzed by Pks13, yielding a β-ketoester that gives, after reduction by the ketoacyl reductase CmrA, the mature mycolate.
10.1128/9781555815783/f0056-01_thmb.gif
10.1128/9781555815783/f0056-01.gif
Image of Figure 5.
Figure 5.

Model of the mycolic acid condensation. R1 and R2 represent long hydrocarbon chains, and X1 and X2 are the unknown intermediate acceptors. The fatty acid molecule bearing R1 is activated as acyl-adenylate (acyl-AMP) by FadD32 to yield the “meromycolate” chain. The other condensation substrate containing the R2 chain is activated by the acyl-CoA carboxylase complex to give the carboxylated intermediate at the origin of the α-branch. Condensation is catalyzed by Pks13, yielding a β-ketoester that gives, after reduction by the ketoacyl reductase CmrA, the mature mycolate.

Citation: Marrakchi H, Bardou F, Lanéelle M, Daffé M. 2008. 4 A Comprehensive Overview of Mycolic Acid Structure and Biosynthesis, p 41-61. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch4
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Tables

4 A Comprehensive Overview of Mycolic Acid Structure and Biosynthesis
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Citation: Marrakchi H, Bardou F, Lanéelle M, Daffé M. 2008. 4 A Comprehensive Overview of Mycolic Acid Structure and Biosynthesis, p 41-61. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch4
/content/10.1128/9781555815783.ch04.ch04tab01
Table 1.
genes involved in fatty acid and mycolic acid synthesis
Generic image for table
Table 1.

genes involved in fatty acid and mycolic acid synthesis

Citation: Marrakchi H, Bardou F, Lanéelle M, Daffé M. 2008. 4 A Comprehensive Overview of Mycolic Acid Structure and Biosynthesis, p 41-61. In Daffé M, Reyrat J, Avenir G (ed), The Mycobacterial Cell Envelope. ASM Press, Washington, DC. doi: 10.1128/9781555815783.ch4

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