Involvement of the fadD33 gene in the growth of Mycobacterium tuberculosis in the liver of BALB/c mice

Rindi, Laura; Fattorini, Lanfranco; Bonanni, Daniela; Iona, Elisabetta; Freer, Giulia; Tan, Dejiang; Dehò, Gianni; Orefici, Graziella; Garzelli, Carlo

doi:10.1099/00221287-148-12-3873

Cited by 38 publications

(28 citation statements)

References 35 publications

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“…In this study, we have identified a genetic locus involved in the assembly of mycobactins, which we propose to annotate as mbt-2. Interestingly, several genes from the mbt-2 cluster were earlier demonstrated to be essential for the growth of mycobacteria (16,17). Our studies here delineate the biochemical functions of all these genes.…”

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confidence: 66%

“…One such interesting cluster contains proteins (FadD33 and FadE14) that showed distinct homology to proteins involved in lipid metabolism. The disruption of fadD33 gene in M. tuberculosis H37Rv had earlier suggested the important role of the gene product in mycobacterial virulence by supporting its replication in the liver (17). Computational analysis of FadD33 protein indicated that this protein was homologous to the newly discovered fatty acyl-AMP ligase (FAAL) proteins from mycobacteria (19).…”

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confidence: 93%

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A genetic locus required for iron acquisition in Mycobacterium tuberculosis

Krithika

Marathe

Saxena

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

124

130

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Mycobactins are a family of membrane-associated siderophores required for Mycobacterium tuberculosis to adapt to its intracellular habitat. These lipophilic siderophores have been recently shown to directly acquire intracellular iron through lipid trafficking. Despite tremendous progress in understanding the assemblyline enzymology of the siderophore biosynthesis, the genes as well as the mechanistic and biochemical principles involved in producing membrane-associated siderophores have not been investigated. Here, we report a biosynthetic locus that incorporates variety of aliphatic chains on the mycobactin skeleton. Cell-free reconstitution studies demonstrate that these acyl chains are directly transferred from a carrier protein on to the -amino group of lysine residue by an unidentified Rv1347c gene product. The unsaturation in the lipidic chain is produced by a novel acyl-acyl carrier protein dehydrogenase, which, in contrast to the conventional acyl-CoA dehydrogenases, is involved in the biosynthetic pathway. MbtG protein then performs the final N6-hydroxylation step. Genome-wide analysis revealed homologues of N-acyl transferase and MbtG in other pathogenic bacteria. Because iron plays a key role in the development of infectious diseases, the biosynthetic pathway described here represents an attractive target for developing new antibacterial agents.biosynthesis ͉ mycobactin ͉ siderophore ͉ acyl-transferase ͉ dehydrogenase

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confidence: 66%

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confidence: 93%

A genetic locus required for iron acquisition in Mycobacterium tuberculosis

Krithika

Marathe

Saxena

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

124

130

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“…Most notable are those described in Enterobacter cloacae and Haemophilus influenzae (112,135). An orthologue of the FACS FadD has been experimentally defined in Mycobacterium tuberculosis (113).…”

Section: Genetic Foundations Of Fatty Acid Transportmentioning

confidence: 99%

Transmembrane Movement of Exogenous Long-Chain Fatty Acids: Proteins, Enzymes, and Vectorial Esterification

Black

DiRusso

2003

Microbiol Mol Biol Rev

212

158

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The processes that govern the regulated transport of long-chain fatty acids across the plasma membrane are quite distinct compared to counterparts involved in the transport of hydrophilic solutes such as sugars and amino acids. These differences stem from the unique physical and chemical properties of long-chain fatty acids. To date, several distinct classes of proteins have been shown to participate in the transport of exogenous long-chain fatty acids across the membrane. More recent work is consistent with the hypothesis that in addition to the role played by proteins in this process, there is a diffusional component which must also be considered. Central to the development of this hypothesis are the appropriate experimental systems, which can be manipulated using the tools of molecular genetics. Escherichia coli and Saccharomyces cerevisiae are ideally suited as model systems to study this process in that both (i) exhibit saturable long-chain fatty acid transport at low ligand concentrations, (ii) have specific membrane-bound and membrane-associated proteins that are components of the transport apparatus, and (iii) can be easily manipulated using the tools of molecular genetics. In both systems, central players in the process of fatty acid transport are fatty acid transport proteins (FadL or Fat1p) and fatty acyl coenzyme A (CoA) synthetase (FACS; fatty acid CoA ligase [AMP forming] [EC 6.2.1.3]). FACS appears to function in concert with FadL (bacteria) or Fat1p (yeast) in the conversion of the free fatty acid to CoA thioesters concomitant with transport, thereby rendering this process unidirectional. This process of trapping transported fatty acids represents one fundamental mechanism operational in the transport of exogenous fatty acids

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“…Mutants which cannot synthesize cyclopropane synthetase (pcaA), isocitrate lyase enzyme (icl), or phospholipases had reduced survival in mice (14,27,39). Likewise, leucine and pantothenate auxotrophic mutants (⌬leuD, ⌬panD) as well as mutants which had defects in lipid or iron metabolism were all attenuated in SCID or normal mice to various degrees (16,25,40,44). Disruption of genes for nonenzyme proteins has also identified additional functional mutants.…”

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A Mutant of Mycobacterium tuberculosis H37Rv That Lacks Expression of Antigen 85A Is Attenuated in Mice but Retains Vaccinogenic Potential

et al. 2004

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The fbpA and fbpB genes encoding the 85A and 85B proteins of Mycobacterium tuberculosis H37Rv, respectively, were disrupted, the mutants were examined for their ability to survive, and the strain lacking 85A (⌬fbpA) was tested for its ability to immunize mice. The ⌬fbpA mutant was attenuated in mice after intravenous or aerosol infection, while replication of the ⌬fbpB mutant was similar to that of the wild type. Complementation of the fbpA gene in ⌬fbpA restored its ability to grow in the lungs of mice. The ⌬fbpA mutant induced a stronger expression of pulmonary mRNA messages in mice for tumor necrosis factor alpha, interleukin-1 beta (IL-1␤), gamma interferon, IL-6, IL-2, and inducible nitric oxide (NO) synthase, which led to its decline, while H37Rv persisted despite strong immune responses. H37Rv and ⌬fbpA both induced NO in macrophages and were equally susceptible to NO donors, although ⌬fbpA was more susceptible in vitro to peroxynitrite and its growth was enhanced by NO inhibitors in mice and macrophages. Aerosol-infected mice, which cleared a low-dose ⌬fbpA infection, resisted a challenge with virulent M. tuberculosis. Mice subcutaneously immunized with ⌬fbpA or Mycobacterium bovis BCG and challenged with M. tuberculosis also showed similar levels of protection, marked by a reduction in the growth of challenged M. tuberculosis. The ⌬fbpA mutant was thus attenuated, unlike ⌬fbpB, but was also vaccinogenic against tuberculosis. Attenuation was incomplete, however, since ⌬fbpA revived in normal mice after 370 days, suggesting that revival was due to immunosenescence but not compensation by the fbpB or fbpC gene. Antigen 85A thus affects susceptibility to peroxynitrite in M. tuberculosis and appears to be necessary for its optimal growth in mice.

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Involvement of the fadD33 gene in the growth of Mycobacterium tuberculosis in the liver of BALB/c mice

Cited by 38 publications

References 35 publications

A genetic locus required for iron acquisition in Mycobacterium tuberculosis

A genetic locus required for iron acquisition in Mycobacterium tuberculosis

Transmembrane Movement of Exogenous Long-Chain Fatty Acids: Proteins, Enzymes, and Vectorial Esterification

A Mutant of Mycobacterium tuberculosis H37Rv That Lacks Expression of Antigen 85A Is Attenuated in Mice but Retains Vaccinogenic Potential

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