Mycolic acid

Mycolic acids are long fatty acids found in the cell walls of the mycolata taxon, a group of bacteria that includes Mycobacterium tuberculosis, the causative agent of the disease tuberculosis. They form the major component of the cell wall of mycolata species. Despite their name, mycolic acids have no biological link to fungi; the name arises from the filamentous appearance their presence gives mycolata under high magnification. The presence of mycolic acids in the cell wall also gives mycolata a distinct gross morphological trait known as "cording." Mycolic acids were first isolated by Stodola et al. in 1938 from an extract of M. tuberculosis.

Mycolic acids are composed of a shorter beta-hydroxy chain with a longer alpha-alkyl side chain. Each molecule contains between 60 and 90 carbon atoms. The exact number of carbons varies by species and can be used as an identification aid. Most mycolic acids also contain various functional groups.

Mycolic Acids of M. tuberculosis

M. tuberculosis produces three main types of mycolic acids: alpha-, methoxy-, and keto-. Alpha-mycolic acids comprise at least 70% of the mycolic acids present in the organism and contain several cyclopropane rings. Methoxy-mycolic acids, which contain several methoxy groups, comprise between 10% and 15% of the mycolic acids in the organism. The remaining 10% to 15% of the mycolic acids are keto-mycolic acids, which contain several ketone groups.

The presence of mycolic acids gives M. tuberculosis many characteristics that defy medical treatment. They lend the organism increased resistance to chemical damage and dehydration, and prevent the effective activity of hydrophobic antibiotics. In addition, the mycolic acids allow the bacterium to grow readily inside macrophages, effectively hiding it from the host's immune system. Mycolate biosynthesis is crucial for survival and pathogenesis of Mycobacterium tuberculosis. The pathway and enzymes have now been elucidated and reported in detail, for example by Takayama et al^[1] and Raman et al^[2] in 2005. Five distinct stages are involved. These were summarised by Bhatt et al^[3] as follows:

• Synthesis of the C26 saturated straight chain fatty acids by Fatty Acid Synthase-I (FAS-I) to provide the α-alkyl branch of the mycolic acids;
• Synthesis of the C56 fatty acids by FAS-II providing the meromycolate backbone;
• Introduction of functional groups to the meromycolate chain by numerous cyclopropane synthases;
• Condensation reaction catalysed by the polyketide synthase Pks13 between the α-branch and the meromycolate chain before a final reduction to generate the mycolic acid; and
• Transfer of mycolic acids to arabinogalactan and other acceptors such as trehalose via the Antigen 85 complex

The fatty acid synthase-I and fatty acid synthase-II pathways producing mycolic acids are linked by the beta-ketoacyl-(acyl-carrier-protein) synthase III enzyme, often designated as mtFabH. This enzyme is the focus of novel inhibitors as therapeutic agents.

The exact structure of mycolic acids appears to be closely linked to the virility of the organism, as modification of the functional groups of the molecule can lead to an attenuation of growth in vivo. Further, individuals with mutations in genes responsible for mycolic acid synthesis exhibit altered cording.

Figure: An example of a mycolic acid from Mycobacterium tuberculosis

Mycolic Acids of Rhodococcus sp.

The mycolic acids of members of the genus Rhodococcus, another member of the mycolata taxon, differ in several ways from those of M. tuberculosis. They contain no functional groups, but instead may have several unsaturated bonds. Two different profiles of Rhodococcus mycolic acids exist. The first has between 28 and 46 carbon atoms with either 0 or 1 unsaturated bond. The second has between 34 and 54 carbon atoms with between 0 and 4 unsaturated bonds. Sutcliffe (1998) has proposed that they are linked to the rest of the cell wall by arabinogalactan molecules.

References

Further reading

• Barry et al. (1998). "Mycolic acids: structure, biosynthesis, and physiological functions." Prog. Lipid Res. 37(3): 143-79.
• Nishiuchi, Baba, and Yano (1999). "Mycolic acids from Rhodococcus, Gordonia, and Dietzia." J. Microbiol. Methods 40: 1-9.
• Sutcliffe (1998). "Cell envelope composition and organization in the genus Rhodococcus." Antonie van Leeuwenhoek 74: 49-58.

External links

• MeSH Mycolic+Acid