Many important issues about the biosynthesis and export pathways of the mycolate-containing compounds remain unresolved. How mycobacteria control and modulate the content and the fine structure of their mycolic acids (MAs)? What are the compositions and structures of the metabolic systems responsible for the production and degradation of MAs and MA-containing compounds? How this metabolism responds to environmental conditions and what regulatory mechanisms are involved? Elucidating these open questions is of paramount importance for understanding the intricate network of events governing the host–pathogen dialogue involving the MAs; they constitute the main aim of this topic.
MA biosynthesis. MAs are the products of a mixed fatty acid synthase/polyketide synthase biosynthesis pathway. The formation of the main extra long 'meromycolic' chain of MAs is dependent upon an original Fatty Acid Synthase type II (FAS-II) elongation multienzyme system. Another enzymatic machinery, the mycolic condensation system, catalyzes the ultimate stage of this pathway. With collaborators, we develop integrative approaches to decipher the compositions, precise functions and structures of these unique protein complexes. We study the enzymatic properties of their individual subunits specific to very long acyl chains and the structural bases of their unprecedented functions. We also investigate their roles in the physiology of mycobacteria and in the virulence of M. tuberculosis. Thanks to this approach, we contribute with others to draw a more comprehensive scheme of this key mycobacterial metabolic pathway.
Regulatory mechanisms of mycolic acid metabolism. It is known that genes involved in MA biosynthesis in M. tuberculosis are downregulated in the macrophage infection model, and several transcription regulators of this pathway, FasR, MabR and FadR, have been identified. Accordingly, our group recently observed that nutrient scarcity, encountered during infection, leads to downregulation of the hadABC genes encoding FAS-II dehydratases along with most of the genes required for the synthesis and transport of mycolates. This adaptation phenomenon partly relies on the bacterial stringent response. Post-translational modifications and notably signaling through Ser/Thr phosphorylation have also recently emerged as a key regulatory mechanism in pathogenic mycobacteria. In particular, we demonstrated with others that the activities of important or essential enzymes of MA biosynthesis and transport pathways are negatively regulated by serine/threonine protein kinases (STPK).
Current collaborators
- Odile Schiltz's group, Institut de Pharmacologie et Biologie Structurale, Toulouse
- Lionel Mourey's group, Institut de Pharmacologie et Biologie Structurale, Toulouse
- Christophe Guilhot's group, Institut de Pharmacologie et Biologie Structurale, Toulouse
- Gwennaele Fichant's group, LMGM-UMR5100, Toulouse
- Patrick Bron's group, Centre de Biochimie Structurale, INSERM U554, Montpellier
- Virginie Molle's group, DIMNP, UMR-5235, Montpellier
- Gwenaëlle André-Leroux, MaiAGE, INRA, Jouy-en-Josas
- Roland Brosch's group, Institut Pasteur, Paris
- Pedro Alzari's group, Institut Pasteur, Paris
- Matthias Wilmanns, EMBL, Hamburg (Germany)
- Hugo Gramajo's group, IBR, CONICET, Rosario (Argentina)
- Tanya Parish's group, Centre for Infectious Disease, London (UK)
- Andrzej Dziembowski's group, Institute of Biochemistry and Biophysics, Warsaw (Poland)
Selected publications
- Lefebvre C et al (2018) HadD, a novel fatty acid synthase type II protein, is essential for alpha- and epoxy-mycolic acid biosynthesis and mycobacterial fitness. Sci Rep 8:6034
- Bazet Lyonnet B et al (2017) Functional reconstitution of the Mycobacterium tuberculosis long-chain acyl-CoA carboxylase from multiple acyl-CoA subunits. FEBS J 284:1110-25
- Slama N et al (2016) The changes in mycolic acid structures caused by hadC mutation have a dramatic effect on virulence of Mycobacterium tuberculosis. Mol Microbiol 99:794-807
- Le N-H et al (2016) Ser/Thr phosphorylation regulates the Fatty Acyl-AMP Ligase activity of FadD32, an essential enzyme in mycolic acid biosynthesis. J Biol Chem 291:22793-805
- Guillet V et al (2016) Insight into Structure-Function Relationships and Inhibition of the Fatty Acyl-AMP Ligase (FadD32) Orthologs from Mycobacteria. J Biol Chem 291:7973-89
- Jamet S et al (2015) Evolution of mycolic acid biosynthesis genes and their regulation during starvation in Mycobacterium tuberculosis. J Bacteriol 197:3797-811
- Gavalda S et al (2014) The polyketide synthase Pks13 catalyzes a novel mechanism of lipid transfer in mycobacteria. Chem Biol 21:1660-9
- Léger M et al (2009) The Dual Function of the Mycobacterium tuberculosis FadD32 Required for Mycolic Acid Biosynthesis. Chem Biol 16:510-519
- Sacco E et al (2007). The missing piece of the type II Fatty Acid Synthase system from Mycobacterium tuberculosis. Proc Natl Acad Sci USA 104: 14628-14633
Selected reviews/book chapters
- Daffé M et al (2017) Mycolic acids: from Chemistry to Biology. In Biogenesis of Fatty Acids, Lipids and Membranes, O Geiger ed, Handbook of Hydrocarbon and Lipid Microbiology series (Springer, Cham)
- Quémard A (2016) New Insights into the Mycolate-Containing Compound Biosynthesis and Transport in Mycobacteria. Trends in Microbiology 24:725-38
- Marrakchi H et al (2014) Mycolic acids: structures, biosynthesis and beyond. Chem Biol 21:67-85