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Mycolic acids are long
fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...
s found in the
cell wall A cell wall is a structural layer surrounding some types of cells, just outside the cell membrane. It can be tough, flexible, and sometimes rigid. It provides the cell with both structural support and protection, and also acts as a filtering mec ...
s of the Mycolata
taxon In biology, a taxon ( back-formation from '' taxonomy''; plural taxa) is a group of one or more populations of an organism or organisms seen by taxonomists to form a unit. Although neither is required, a taxon is usually known by a particular n ...
, a group of
bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...
that includes ''
Mycobacterium tuberculosis ''Mycobacterium tuberculosis'' (M. tb) is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, ''M. tuberculosis'' has an unusual, waxy coating on it ...
'', the causative agent of the disease
tuberculosis Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, ...
. They form the major component of the cell wall of mycolata species. Despite their name, mycolic acids have no biological link to
fungi A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately fr ...
; 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 longer beta-hydroxy chain with a shorter alpha-
alkyl In organic chemistry, an alkyl group is an alkane missing one hydrogen. The term ''alkyl'' is intentionally unspecific to include many possible substitutions. An acyclic alkyl has the general formula of . A cycloalkyl is derived from a cycloa ...
side chain In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called the "main chain" or backbone. The side chain is a hydrocarbon branching element of a molecule that is attached to a ...
. Each molecule contains between 60 and 90
carbon Carbon () is a chemical element with the symbol C and atomic number 6. It is nonmetallic and tetravalent—its atom making four electrons available to form covalent chemical bonds. It belongs to group 14 of the periodic table. Carbon ma ...
atoms. The exact number of carbons varies by species and can be used as an identification aid. Most mycolic acids also contain various
functional group In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the r ...
s.


Mycolic acids of ''M. 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 Cyclopropane is the cycloalkane with the molecular formula (CH2)3, consisting of three methylene groups (CH2) linked to each other to form a ring. The small size of the ring creates substantial ring strain in the structure. Cyclopropane itself i ...
rings. Methoxy-mycolic acids, which contain several
methoxy In organic chemistry, a methoxy group is the functional group consisting of a methyl group bound to oxygen. This alkoxy group has the formula . On a benzene ring, the Hammett equation classifies a methoxy substituent at the ''para'' position a ...
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 In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double b ...
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 A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are n ...
antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...
s and
biocides A biocide is defined in the European legislation as a chemical substance or microorganism intended to destroy, deter, render harmless, or exert a controlling effect on any harmful organism. The US Environmental Protection Agency (EPA) uses a sl ...
. Mycolic acids also allow the bacterium to grow inside
macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
s, effectively hiding it from the host
immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
. Mycolate biosynthesis is crucial for survival and pathogenesis of ''M. tuberculosis''. The pathway and enzymes have been elucidated and reported in detail. Five distinct stages are involved. These were summarised as follows: * Synthesis of the C26 saturated straight chain fatty acids by the enzyme 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 Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...
Pks13 between the α-branch and the meromycolate chain before a final reduction by the enzyme corynebacterineae mycolate reductase A (CmrA) 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 In enzymology, a β-ketoacyl- cyl-carrier-proteinsynthase III () is an enzyme that catalyzes the chemical reaction :acetyl-CoA + malonyl- acyl_carrier_protein">/nowiki> acyl_carrier_protein">/nowiki>acyl_carrier_protein">acyl_carrier_protein. ...
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 Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...
. The natural extracts are however chemically heterogeneous and inflammatory. By
organic synthesis Organic synthesis is a special branch of chemical synthesis and is concerned with the intentional construction of organic compounds. Organic molecules are often more complex than inorganic compounds, and their synthesis has developed into one o ...
, 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
cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...
ular immune response ( Th1 and Th17), so studies are ongoing to use this subclass as an
adjuvant In pharmacology, an adjuvant is a drug or other substance, or a combination of substances, that is used to increase the efficacy or potency of certain drugs. Specifically, the term can refer to: * Adjuvant therapy in cancer management * Analgesi ...
for
vaccination Vaccination is the administration of a vaccine to help the immune system develop immunity from a disease. Vaccines contain a microorganism or virus in a weakened, live or killed state, or proteins or toxins from the organism. In stimulat ...
. 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 Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and p ...
''. Further, individuals with
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
s in genes responsible for mycolic acid synthesis exhibit altered cording.


Clinical relevance

An international multi-centre study has proved that
delamanid Delamanid, sold under the brand name Deltyba, is a medication used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, for active multidrug-resistant tuberculosis. It is taken by mouth. Common side eff ...
(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 Culture conversion is a diagnostic criteria indicating the point at which samples taken from a person infected with a tuberculosis can no longer produce tuberculosis cell cultures. Culture conversion is a positive prognostic Prognosis (Greek: π ...
in
multi-drug-resistant tuberculosis Multidrug-resistant tuberculosis (MDR-TB) is a form of tuberculosis (TB) infection caused by bacteria that are resistant to treatment with at least two of the most powerful first-line anti-TB medications (drugs): isoniazid and rifampin. Some ...
(MDRTB) at 2 months.


Mycolic acids of ''Rhodococcus'' sp.

The mycolic acids of members of the
genus Genus ( plural genera ) is a taxonomic rank used in the biological classification of living and fossil organisms as well as viruses. In the hierarchy of biological classification, genus comes above species and below family. In binomial nom ...
'' 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 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.


References


Further reading

* * * *


External links

* {{Bacteria Fatty acids Cyclopropanes