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Fatty acid biosynthesis in Mycobacterium tuberculosis: lateral gene transfer, adaptive evolution, and gene duplication.

ABSTRACT: Mycobacterium tuberculosis is a high GC Gram-positive member of the actinobacteria. The mycobacterial cell wall is composed of a complex assortment of lipids and is the interface between the bacterium and its environment. The biosynthesis of fatty acids plays an essential role in the formation of cell wall components, in particular mycolic acids, which have been targeted by many of the drugs used to treat M. tuberculosis infection. M. tuberculosis has approximately 250 genes involved in fatty acid metabolism, a much higher proportion than in any other organism. In silico methods have been used to compare the genome of M. tuberculosis CDC1551 to a database of 58 complete bacterial genomes. The resulting alignments were scanned for genes specifically involved in fatty acid biosynthetic pathway I. Phylogenetic analysis of these alignments was used to investigate horizontal gene transfer, gene duplication, and adaptive evolution. It was found that of the eight gene families examined, five of the phylogenies reconstructed suggest that the actinobacteria have a closer relationship with the alpha-proteobacteria than expected. This is either due to either an ancient transfer of genes or deep paralogy and subsequent retention of the genes in unrelated lineages. Additionally, adaptive evolution and gene duplication have been an influence in the evolution of the pathway. This study provides a key insight into how M. tuberculosis has developed its unique fatty acid synthetic abilities.

SUBMITTER: Kinsella RJ

PROVIDER: S-EPMC193559 | biostudies-literature | 2003 Sep

REPOSITORIES: biostudies-literature

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Fatty acid biosynthesis in Mycobacterium tuberculosis: lateral gene transfer, adaptive evolution, and gene duplication.

Kinsella Rhoda J RJ Fitzpatrick David A DA Creevey Christopher J CJ McInerney James O JO

Proceedings of the National Academy of Sciences of the United States of America 20030813 18

Mycobacterium tuberculosis is a high GC Gram-positive member of the actinobacteria. The mycobacterial cell wall is composed of a complex assortment of lipids and is the interface between the bacterium and its environment. The biosynthesis of fatty acids plays an essential role in the formation of cell wall components, in particular mycolic acids, which have been targeted by many of the drugs used to treat M. tuberculosis infection. M. tuberculosis has approximately 250 genes involved in fatty ac ...[more]

PMID: 12917487

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Project description:Current models of horizontal gene transfer (HGT) in mycobacteria are based on "distributive conjugal transfer" (DCT), an HGT type described in the fast-growing, saprophytic model organism Mycobacterium smegmatis, which creates genome mosaicism in resulting strains and depends on an ESX-1 type VII secretion system. In contrast, only few data on interstrain DNA transfer are available for tuberculosis-causing mycobacteria, for which chromosomal DNA transfer between two Mycobacterium canettii strains was reported, a process which, however, was not observed for Mycobacterium tuberculosis strains. Here, we have studied a wide range of human- and animal-adapted members of the Mycobacterium tuberculosis complex (MTBC) using an optimized filter-based mating assay together with three selected strains of M. canettii that acted as DNA recipients. Unlike in previous approaches, we obtained a high yield of thousands of recombinants containing transferred chromosomal DNA fragments from various MTBC donor strains, as confirmed by whole-genome sequence analysis of 38 randomly selected clones. While the genome organizations of the obtained recombinants showed mosaicisms of donor DNA fragments randomly integrated into a recipient genome backbone, reminiscent of those described as being the result of ESX-1-mediated DCT in M. smegmatis, we observed similar transfer efficiencies when ESX-1-deficient donor and/or recipient mutants were used, arguing that in tubercle bacilli, HGT is an ESX-1-independent process. These findings provide new insights into the genetic events driving the pathoevolution of M. tuberculosis and radically change our perception of HGT in mycobacteria, particularly for those species that show recombinogenic population structures despite the natural absence of ESX-1 secretion systems.IMPORTANCE Data on the bacterial sex-mediated impact on mycobacterial evolution are limited. Hence, our results presented here are of importance as they clearly demonstrate the capacity of a wide range of human- and animal-adapted Mycobacterium tuberculosis complex (MTBC) strains to transfer chromosomal DNA to selected strains of Mycobacterium canettii Most interestingly, we found that interstrain DNA transfer among tubercle bacilli was not dependent on a functional ESX-1 type VII secretion system, as ESX-1 deletion mutants of potential donor and/or recipient strains yielded numbers of recombinants similar to those of their respective parental strains. These results argue that HGT in tubercle bacilli is organized in a way different from that of the most widely studied Mycobacterium smegmatis model, a finding that is also relevant beyond tubercle bacilli, given that many mycobacteria, like, for example, Mycobacterium avium or Mycobacterium abscessus, are naturally devoid of an ESX-1 secretion system but show recombinogenic, mosaic-like genomic population structures.

Project description:UnlabelledMycobacterium 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.ImportanceMycobacterium 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.

Dataset Information

Fatty acid biosynthesis in Mycobacterium tuberculosis: lateral gene transfer, adaptive evolution, and gene duplication.

Publications

Fatty acid biosynthesis in Mycobacterium tuberculosis: lateral gene transfer, adaptive evolution, and gene duplication.

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