If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Biosynthesis → Fatty Acid and Lipid Biosynthesis → Fatty Acid Biosynthesis|
Some taxa known to possess this pathway include : Mycobacterium tuberculosis H37Rv
Expected Taxonomic Range: Mycobacteriaceae
Mycolic acids are the hallmark of the cell envelope of Mycobacterium tuberculosis and related species and genera. They comprise a homologous series of C60-C90 (2R)-alkyl-(3R)-hydroxy very long-chain fatty acids, and are found as either esters of an arabinogalactan or as free lipids in the form of trehalose dimycolate (TDM). Both forms contribute to forming the two leaflets of the mycobacterial outer membrane, also called the mycomembrane, which protects the organism from antibiotics and the host's immune system [Takayama05, Bhatt07a, Schweizer04].
There is a significant variability in the structure of mycolic acids among different species. Acids from
Corynebacterium species contain 22-38 carbon atoms,
Amycolicicoccus spp. contain 30-36,
Dietzia spp. contain 34-38,
The acids are formed by a Claisen-type condensation of two components - the meromycolic chain and a fatty acid. Several structural classes of mycolic acids exist. In Mycobacterium tuberculosis the most apolar ones, known as α-mycolic acids, contain 74-80 carbon atoms (out of which 22-26 carbons are located in the fatty acid moiety and the rest on the mero-chain) and generally two double bonds (that can be in either cis- or trans-configuration) or two cis-cyclopropyl groups located in the meromycolic chain. The cyclopropane rings are believed to protect the organism from oxidative stress [Takayama05]. α-Mycolic acids usually comprise more than 70 percent of the total mycolic acids in the cell.
Other classes are defined by additional oxygen functions located in the distal part of the meromycolic chain, and include keto-, methoxy-, wax ester-, epoxy-, and hydroxy-types. In Mycobacterium tuberculosis the oxygenated mycolic acids (keto-, methoxy-, and hydroxy-types) contain ~84-88 carbon atoms, and are thus four to six carbons longer than the α-mycolic acids from the same strains.
About This Pathway
The biosynthesis of mycolic acids could be divided conceptually into three parts: the biosynthesis of the fatty acid moiety, the biosynthesis of the mero-acid moiety, and the condensation of both parts.
The fatty acid moiety is produced by a "eukaryotic-like" multifunctional FAS-I enzyme complex (encoded by the Rv2524C gene), which produces C24-C26 acids (lignocerotate and cerotate), which are used as the "α branch" of the mycolic acids following carboxylation at position 2.
At the level of C22 ( trans-docos-2-enoyl-[acp]) an isomerase encoded by echA10 or echA11 acts on some of the acids, transferring the double bond at position 2, which is introduced by the fatty acid dehydratase domain, to position 3. While those acids that were not affected by the isomerase continue elongation by FAS-I to the level of C26, the desaturated acid that result from isomerization, trans-docos-3-enoyl-[acp], is no longer recognized by the FAS I enzyme. Instead, it is processed by a second, bacterial-like FAS-II system, which is composed of multiple discrete soluble enzymes (encoded by kasA/ kasB, fabG1, meromycolic acid 3-hydroxyacyl-[acyl-carrier-protein] dehydratase I/ meromycolic acid 3-hydroxyacyl-[acyl-carrier-protein] dehydratase II, and inhA. The longer fatty acids generated by FAS II eventually form the mero-chain moieties of the mycolic acids.
Although the two FAS systems differ in their molecular organizations, substrates, and carrier specificities, they share the typical reaction sequence, with an iterative series of reactions built on successive additions of a two-carbon unit from malonyl-CoA (FAS I) or malonyl-[acp] (FAS II) to the nascent acyl group.
During elongation by the FAS-II system, continuous introduction of 2-carbon units upstream of the the double bond at position 3 results in its "migration" farther from the carboxylate (to positions 5, 7, 9 etc). At the level of C35 the isomerase (encoded by echA10 or echA11) acts again, shifting another double bond from position 2 to position 3. This action of the isomerase results in a second branch in the pathway, where some of the acids continue with an additional double bond, while others continue without it. Both continue to be elongated by the FAS-II system. The acids that escaped the isomeization at the C35 level undergo an isomerization at the level of C40. This isomerization event does not result in a branch in the pathway.
Following completion of the elongation process, the acids are modified by several additional enzymes which introduce methoxy groups and convert double bonds to cyclopropyl groups (including mmaA1, mmaA2, mmaA3, mmaA4, pcaA, cmaA2). The final modified acids, as well as the final product of the FAS-I system, are then transferred from their [acp] and CoA carriers (respectively) to a polyketide enzyme, encoded by the pks13 gene, which catalyzes their condensation into a mycolic acid [Portevin04, Trivedi04].
Additional enzymes catalyze the conjugation of the mycolic acids first to D-mannopyranosyl-1-phosphoheptaprenol and subsequently to α,α-trehalose 6-phosphate. Following the removal of the phosphate, the free mycolic acid is exported to the periplasm, where it is attached to arabinogalactan in the cell wall, or to a second mycolic acid, forming a dimycolate.
Superpathways: superpathway of mycolate biosynthesis
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