title: Evolution of Mycolic Acid Biosynthesis Genes and Their Regulation during Starvation in Mycobacterium tuberculosis.
abstract: Mycobacterium tuberculosis, the etiological agent of tuberculosis, is a Gram-positive bacterium with a unique cell envelope composed of an essential outer membrane. Mycolic acids, which are very-long-chain (up to C100) fatty acids, are the major components of this mycomembrane. The enzymatic pathways involved in the biosynthesis and transport of mycolates are fairly well documented and are the targets of the major antituberculous drugs. In contrast, only fragmented information is available on the expression and regulation of the biosynthesis genes. In this study, we report that the hadA, hadB, and hadC genes, which code for the mycolate biosynthesis dehydratase enzymes, are coexpressed with three genes that encode proteins of the translational apparatus. Consistent with the well-established control of the translation potential by nutrient availability, starvation leads to downregulation of the hadABC genes along with most of the genes required for the synthesis, modification, and transport of mycolates. The downregulation of a subset of the biosynthesis genes is partially dependent on RelMtb, the key enzyme of the stringent response. We also report the phylogenetic evolution scenario that has shaped the current genetic organization, characterized by the coregulation of the hadABC operon with genes of the translational apparatus and with genes required for the modification of the mycolates.
  
  
  OBJECTIVE
  Mycobacterium tuberculosis infects one-third of the human population worldwide, and despite the available therapeutic arsenal, it continues to kill millions of people each year. There is therefore an urgent need to identify new targets and develop a better understanding of how the bacterium is adapting itself to host defenses during infection. A prerequisite of this understanding is knowledge of how this adaptive skill has been implanted by evolution. Nutrient scarcity is an environmental condition the bacterium has to cope with during infection. In many bacteria, adaptation to starvation relies partly on the stringent response. M. tuberculosis's unique outer membrane layer, the mycomembrane, is crucial for its viability and virulence. Despite its being the target of the major antituberculosis drugs, only scattered information exists on how the genes required for biosynthesis of the mycomembrane are expressed and regulated during starvation. This work has addressed this issue as a step toward the identification of new targets in the fight against M. tuberculosis.
authors.affiliation: Centre National de la Recherche Scientifique, IPBS, UMR 5089, Toulouse, France Université Toulouse, UPS, Toulouse, France.
authors.forename: Stevie
authors.initials: S
authors.lastname: Jamet
authors.affiliation: Centre National de la Recherche Scientifique, LMGM, UMR 5100, Toulouse, France Université Toulouse, UPS, Toulouse, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Quentin
authors.affiliation: Centre National de la Recherche Scientifique, IPBS, UMR 5089, Toulouse, France Université Toulouse, UPS, Toulouse, France.
authors.forename: Coralie
authors.initials: C
authors.lastname: Coudray
authors.affiliation: Centre National de la Recherche Scientifique, IPBS, UMR 5089, Toulouse, France Centre National de la Recherche Scientifique, LMGM, UMR 5100, Toulouse, France Université Toulouse, UPS, Toulouse, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Texier
authors.affiliation: Centre National de la Recherche Scientifique, IPBS, UMR 5089, Toulouse, France Université Toulouse, UPS, Toulouse, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Laval
authors.affiliation: Centre National de la Recherche Scientifique, IPBS, UMR 5089, Toulouse, France Université Toulouse, UPS, Toulouse, France.
authors.forename: Mamadou
authors.initials: M
authors.lastname: Daffé
authors.affiliation: Centre National de la Recherche Scientifique, LMGM, UMR 5100, Toulouse, France Université Toulouse, UPS, Toulouse, France Gwennaele.Fichant@ibcg.biotoul.fr kaymeuang.cam@ipbs.fr.
authors.forename: Gwennaele
authors.initials: G
authors.lastname: Fichant
authors.affiliation: Centre National de la Recherche Scientifique, IPBS, UMR 5089, Toulouse, France Université Toulouse, UPS, Toulouse, France Gwennaele.Fichant@ibcg.biotoul.fr kaymeuang.cam@ipbs.fr.
authors.forename: Kaymeuang
authors.initials: K
authors.lastname: Cam
mesh_terms: D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000502:physiology; D015536:Down-Regulation; D064429:Fatty Acid Synthases / Q000096:biosynthesis / Q000235:genetics; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics*; D006836:Hydro-Lyases / Q000096:biosynthesis / Q000235:genetics*; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000378:metabolism*; D009171:Mycolic Acids / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000235:genetics; D013217:Starvation
chemical_list: D001426:Bacterial Proteins; D009171:Mycolic Acids; D064429:Fatty Acid Synthases; D006836:Hydro-Lyases; C023926:mycolate synthetase