Mycolic acid

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Mycolic acids are long fatty acids found in the cell walls of Mycobacteriales 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 many Mycobacteriales species. [1] Despite their name, mycolic acids have no biological link to fungi; the name arises from the filamentous appearance their presence gives Mycobacteriales under high magnification. The presence of mycolic acids in the cell wall also gives Mycobacteriales 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.

Contents

Mycolic acids are composed of a longer beta-hydroxy chain with a shorter 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

Mycolic acids in Mycobacterium tuberculosis. Mycobacterium mycolic acids.svg
Mycolic acids in Mycobacterium tuberculosis.

M. tuberculosis produces three main types of mycolic acids: alpha-, methoxy-, and keto-. Alpha-mycolic acids make up at least 70% of the mycolic acids of the organism and contain several cyclopropane rings. Methoxy-mycolic acids, which contain several methoxy groups, constitute 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.

Mycolic acids impart M. tuberculosis with unique properties that defy medical treatment. They make the organism more resistant to chemical damage and dehydration, and limit the effectiveness of hydrophilic antibiotics and biocides. [2] Mycolic acids also allow the bacterium to grow inside macrophages, effectively hiding it from the host immune system. Mycolate biosynthesis is crucial for survival and pathogenesis of M. tuberculosis. The pathway and enzymes have been elucidated and reported in detail. [3] [4] Five distinct stages are involved. These were summarised as follows: [5]

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. Novel inhibitors of this enzyme could potentially be used as therapeutic agents.

The mycolic acids show interesting inflammation controlling properties. A clear tolerogenic response was promoted by natural mycolic acids in experimental asthma. [7] The natural extracts are however chemically heterogeneous and inflammatory. By organic synthesis, the different homologues from the natural mixture could be obtained in pure form and tested for biological activity. One subclass proved to be a very good suppressor of asthma, through a totally new mode of action. These compounds are now under further investigation. A second subclass triggered a cellular immune response (Th1 and Th17), so studies are ongoing to use this subclass as an adjuvant for vaccination.

The exact structure of mycolic acids appears to be closely linked to the virulence 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.

Clinical relevance

An international multi-centre study has proved that delamanid (OPC-67683), a new agent derived from the nitro-dihydro-imidazooxazole class of compounds that inhibits mycolic acid synthesis, can increase the rate of sputum culture conversion in multi-drug-resistant tuberculosis (MDRTB) at 2 months. [8]

Beyond M. tuberculosis

Mycolic acids with different sizes and chemical modifications are found throughout Mycobacteriales. [9]

Mycobacterium

Most attention have been traditionally devoted to the mycolic acids of Mycobacterium species, which display great variation in length and modifications. Modifications not seen in M. tuberculosis include: [9]

Rhodococcus

The mycolic acids of members of the genus Rhodococcus 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 bonds. 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.

Related Research Articles

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<i>Mycobacterium</i> Genus of bacteria

Mycobacterium is a genus of over 190 species in the phylum Actinomycetota, assigned its own family, Mycobacteriaceae. This genus includes pathogens known to cause serious diseases in mammals, including tuberculosis and leprosy in humans. The Greek prefix myco- means 'fungus', alluding to this genus' mold-like colony surfaces. Since this genus has cell walls with a waxy lipid-rich outer layer that contains high concentrations of mycolic acid, acid-fast staining is used to emphasize their resistance to acids, compared to other cell types.

<span class="mw-page-title-main">Rifamycin</span> Group of antibiotics

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<span class="mw-page-title-main">Nicotinamide adenine dinucleotide phosphate</span> Chemical compound

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In molecular biology, biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. This process often consists of metabolic pathways. Some of these biosynthetic pathways are located within a single cellular organelle, while others involve enzymes that are located within multiple cellular organelles. Examples of these biosynthetic pathways include the production of lipid membrane components and nucleotides. Biosynthesis is usually synonymous with anabolism.

<span class="mw-page-title-main">Glyoxylate cycle</span> Series of interconnected biochemical reactions

The glyoxylate cycle, a variation of the tricarboxylic acid cycle, is an anabolic pathway occurring in plants, bacteria, protists, and fungi. The glyoxylate cycle centers on the conversion of acetyl-CoA to succinate for the synthesis of carbohydrates. In microorganisms, the glyoxylate cycle allows cells to use two carbons, such as acetate, to satisfy cellular carbon requirements when simple sugars such as glucose or fructose are not available. The cycle is generally assumed to be absent in animals, with the exception of nematodes at the early stages of embryogenesis. In recent years, however, the detection of malate synthase (MS) and isocitrate lyase (ICL), key enzymes involved in the glyoxylate cycle, in some animal tissue has raised questions regarding the evolutionary relationship of enzymes in bacteria and animals and suggests that animals encode alternative enzymes of the cycle that differ in function from known MS and ICL in non-metazoan species.

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<span class="mw-page-title-main">Isocitrate lyase</span>

Isocitrate lyase, or ICL, is an enzyme in the glyoxylate cycle that catalyzes the cleavage of isocitrate to succinate and glyoxylate. Together with malate synthase, it bypasses the two decarboxylation steps of the tricarboxylic acid cycle and is used by bacteria, fungi, and plants.

<span class="mw-page-title-main">Beta-ketoacyl-ACP synthase III</span> Enzyme

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References

  1. Gupta, Radhey S. (22 February 2019). "Commentary: Genome-Based Taxonomic Classification of the Phylum Actinobacteria". Frontiers in Microbiology. 10. doi: 10.3389/fmicb.2019.00206 . PMC   6395429 . Mycolic acids are important constituents of the cell envelopes of most members.
  2. Lambert, PA (2002). "Cellular impermeability and uptake of biocides and antibiotics in Gram-positive bacteria and mycobacteria". J Appl Microbiol. 92: 46S–54S. doi:10.1046/j.1365-2672.92.5s1.7.x. PMID   12000612. S2CID   24067247.
  3. Takayama, K.; Wang, C.; Besra, G. S. (2005). "Pathway to Synthesis and Processing of Mycolic Acids in Mycobacterium tuberculosis". Clinical Microbiology Reviews. 18 (1): 81–101. doi:10.1128/CMR.18.1.81-101.2005. PMC   544180 . PMID   15653820.
  4. Raman, K.; Rajagopalan, P.; Chandra, N. (2005). "Flux Balance Analysis of Mycolic Acid Pathway: Targets for Anti-Tubercular Drugs". PLOS Computational Biology. 1 (5): e46. Bibcode:2005PLSCB...1...46R. doi: 10.1371/journal.pcbi.0010046 . PMC   1246807 . PMID   16261191.
  5. Bhatt, A.; Molle, V.; Besra, G. S.; Jacobs, W. R.; Kremer, L. (2007). "The Mycobacterium tuberculosis FAS-II condensing enzymes: Their role in mycolic acid biosynthesis, acid-fastness, pathogenesis and in future drug development". Molecular Microbiology. 64 (6): 1442–1454. doi: 10.1111/j.1365-2958.2007.05761.x . PMID   17555433. S2CID   32586686.
  6. Lea-Smith, David J; James S. Pyke; Dedreia Tull; Malcolm J. McConville; Ross L. Coppel; Paul K. Crellin (2007). "The Reductase That Catalyzes Mycolic Motif Synthesis Is Required for Efficient Attachment of Mycolic Acids to Arabinogalactan". Journal of Biological Chemistry. 282 (15): 11000–11008. doi: 10.1074/jbc.M608686200 . PMID   17308303.
  7. Korf, J. E.; Pynaert, G.; Tournoy, K.; Boonefaes, T.; Van Oosterhout, A.; Ginneberge, D.; Haegeman, A.; Verschoor, J. A.; De Baetselier, P.; Grooten, J. (2006). "Macrophage Reprogramming by Mycolic Acid Promotes a Tolerogenic Response in Experimental Asthma". American Journal of Respiratory and Critical Care Medicine. 174 (2): 152–160. doi:10.1164/rccm.200507-1175OC. PMID   16675779.
  8. Gler, M. T.; Skripconoka, V.; Sanchez-Garavito, E.; Xiao, H.; Cabrera-Rivero, J. L.; Vargas-Vasquez, D. E.; Gao, M.; Awad, M.; Park, S. K.; Shim, T. S.; Suh, G. Y.; Danilovits, M.; Ogata, H.; Kurve, A.; Chang, J.; Suzuki, K.; Tupasi, T.; Koh, W. J.; Seaworth, B.; Geiter, L. J.; Wells, C. D. (2012). "Delamanid for Multidrug-Resistant Pulmonary Tuberculosis". New England Journal of Medicine. 366 (23): 2151–2160. doi: 10.1056/NEJMoa1112433 . PMID   22670901.
  9. 1 2 Marrakchi, Hedia; Lanéelle, Marie-Antoinette; Daffé, Mamadou (January 2014). "Mycolic Acids: Structures, Biosynthesis, and Beyond". Chemistry & Biology. 21 (1): 67–85. doi: 10.1016/j.chembiol.2013.11.011 .

Further reading