ReviewThe biosynthesis of mycolic acids by Mycobacteria: current and alternative hypotheses
Section snippets
A chemist's point of view
Several important reviews on the biosynthesis of mycobacterial lipids, in particular of mycolic acids, have been published recently [1], [2], [3]. This knowledge of mycolic acid biosynthesis has made excellent progress recently thanks to the use of the methods and concepts of molecular biology and genetics.
However, these results rely on older publications, essentially chemical, containing structural descriptions or interpretations of the reaction results found. In the use of these older
General formulae and diversity of the mycolates
All the mycobacteria synthesize mycolic acids, typical structures of which are shown in Fig. 1. Their structures are characterised by the presence of a long linear carbon chain (about 60–90 carbon atoms, according to the species). In the case of mycolic acids from Mycobacteria, the vicinal carboxyl and hydroxyl groups are on carbons 23 and 24 (±2) respectively. The part of the molecule from the terminal methyl to the carbon atom bearing the hydroxyl group is called meromycolic chain. The
Metabolic connections between mycolates.
For a long time, the structural analogies between all the different mycolic acids of same strain, has led to proposals for metabolic connections between them [6], [15]. Such metabolism has been clearly demonstrated only in the case of keto-mycolates which can give rise to carboxy-mycolates esterified by 2-octadecanol or 2-eicosanol. These esters have been named wax esters or wax mycolates (Fig. 1), and were isolated mainly as monoglycerides [15]. They have been found in most other derivatives
Introduction of methyl branches and cyclopropane rings
In several strains of mycobacteria (those with slow growth, usually pathogenic), the double bonds are replaced by cyclopropane rings. Saprophytic strains (fast growth) are also able to make cyclopropanic mycolates, when their cultures become old. The replacement of a double bond by a cyclopropane ring in a mycolate produced by M. smegmatis suggested a metabolic relationship between the two types of mycolic acids, by analogy with similar reactions [6], such as the transformation of cis-vaccenic
Implication of S-adenosyl methionine
It has been thought that all the methylations on mycolate chains are derived from methionine, most probably in the form of S-adenosyl methionine. But the substrate of the methylations, which sometimes seems to be obvious, is most often assumed by analogies rather than proven. These analogies seem to be more convincing in the case of the formation of a cyclopropane ring than in the two other cases, that concern the addition of a methyl group to a double bond either with its concomitant
Different interpretations of the published results
The results of the above mentioned research have been interpreted by their authors in relation to the hypothesis that an unsaturated meromycolate, built by elongation by C2 units, is the precursor of every meromycolate. Furthermore, the experiments were often designed to illustrate this hypothesis, which was, in course, strengthened by the results. In such a context, the intervention of the methyl-transferases is dependent on the synthesis of the unsaturated meromycolates, and the reaction is
Coexistence of two ways for the mycolic acid biosynthesis?
After all the above discussion, the elongation hypothesis keeps its validity. The isolation of enzymes used in the synthesis of very long chain fatty acids (up to 30 carbon atoms) strengthens this hypothesis [56]. But it still remains to be proved that such fatty acids play a role in mycolate synthesis. Until now, it was considered that all the species of mycobacteria used a unique biosynthetic complex system to construct the carbon linear backbone of all meromycolates, the different structures
Conclusion
Previous papers concerning the biosynthesis of mycolic acids assumed a biosynthetic scheme deduced from experimental facts, by analogy with known biochemical reactions. But the same experimental facts can be interpreted according to other hypotheses, some of which are discussed here. The choice between the two different hypotheses requires experiments specifically designed to distinguish between them. The possibility that some mycobacteria can use more than one pathway for the biosynthesis of
Acknowledgments
The authors are grateful to Mrs. Jackie Lecointe, the librarian of the Institut de Biologie Cellulaire et Génétique (CNRS, Toulouse), for her kind help for collecting information.
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