Mycolic Acid Biosynthesis in Mycobacterial Systems

Mycolic acids are long-chain α-alkyl, β-hydroxy fatty acids that form a defining component of the mycobacterial cell envelope. Their complex biosynthesis involves two fatty acid synthase systems (FAS-I and FAS-II) to generate meromycolic and α-branches, activation of meromycolic chains by an acyl-AMP ligase, condensation of both branches by a multi-domain polyketide synthase, and subsequent transfer of mature mycolates onto the arabinogalactan–peptidoglycan complex. This multi-step pathway underpins cell-wall impermeability, contributes to virulence, and confers resistance to many antibiotics. Recent structural and mechanistic studies have illuminated the interplay between key enzymes, revealing conformational changes during activation and condensation, and establishing assays for inhibitor screening. Better understanding of each catalytic step not only clarifies cell-envelope assembly but also highlights multiple targets for the development of novel antitubercular agents.

Research from Nature Portfolio

High-resolution structural analysis of the acyl-AMP ligase central to mycolic acid activation has provided a detailed view of its catalytic cycle. The enzyme crystallises in both apo and ATP-bound conformations, exposing a cleft at the interdomain interface where nucleotide binding induces local rearrangements. Comparative mapping of substrate and cofactor sites has identified tunnels for meromycolic acid and phosphopantetheine binding. These insights into domain motions and ligand interactions supply a robust framework for rational design of small molecules aimed at blocking fatty-acid activation, thereby arresting mycolic acid synthesis at its first committed step.

Mycolic Acid Biosynthesis in Mycobacterial Systems publication trend

The graph below shows the total number of articles in mycolic acid biosynthesis in mycobacterial systems across all publications each year (not limited to Nature Index journals).

Technical terms

Mycolic acids: Long α-alkyl, β-hydroxy fatty acids unique to mycobacterial cell envelopes.

FAS-I and FAS-II: Two fatty acid synthase systems that produce basic acyl building blocks and meromycolic chains, respectively.

Acyl-AMP ligase (e.g. FadD32): Enzyme that activates long-chain fatty acids by adenylation, preparing them for transfer to carrier proteins.

Polyketide synthase 13 (Pks13): Multi-domain enzyme that condenses activated meromycolic and α-branches to form mycolic acid precursors.

Thioesterase domain: Catalytic module within Pks13 responsible for releasing the mature mycolic precursor from the enzyme complex.

References

1. Crystal structure of FadD32, an enzyme essential for mycolic acid biosynthesis in mycobacteria. Scientific Reports (2015).
2. Insight into Structure-Function Relationships and Inhibition of the Fatty Acyl-AMP Ligase (FadD32) Orthologs from Mycobacteria*. Journal of Biological Chemistry (2016).
3. Identification and Optimization of Novel Inhibitors of the Polyketide Synthase 13 Thioesterase Domain with Antitubercular Activity. Journal of Medicinal Chemistry (2023).
4. In Silico Development of Novel Benzofuran-1,3,4-Oxadiazoles as Lead Inhibitors of M. tuberculosis Polyketide Synthase 13. Pharmaceuticals (2023).
5. The Pks13/FadD32 Crosstalk for the Biosynthesis of Mycolic Acids in Mycobacterium tuberculosis *. Journal of Biological Chemistry (2009).