The Phosphatidyl-myo-Inositol Mannosyltransferase PimA Is Essential for Mycobacterium tuberculosis Growth In Vitro and In Vivo

@article{Boldrin2014ThePM,
  title={The Phosphatidyl-myo-Inositol Mannosyltransferase PimA Is Essential for Mycobacterium tuberculosis Growth In Vitro and In Vivo},
  author={Francesca Boldrin and M. Ventura and G. Degiacomi and S. Ravishankar and C. Sala and Zuzana Svetl{\'i}kov{\'a} and Anisha Ambady and N. Dhar and Jana Kordul{\'a}kov{\'a} and Ming Zhang and Agnese Serafini and V. G. Vishwas and Gaëlle S. Kolly and Naveen Kumar and G. Pal{\`u} and M. Guerin and K. Miku{\vs}ov{\'a} and S. Cole and R. Manganelli},
  journal={Journal of Bacteriology},
  year={2014},
  volume={196},
  pages={3441 - 3451}
}
ABSTRACT The cell envelope of Mycobacterium tuberculosis contains glycans and lipids of peculiar structure that play prominent roles in the biology and pathogenesis of tuberculosis. Consequently, the chemical structure and biosynthesis of the cell wall have been intensively investigated in order to identify novel drug targets. Here, we validate that the function of phosphatidyl-myo-inositol mannosyltransferase PimA is vital for M. tuberculosis in vitro and in vivo. PimA initiates the… Expand
The Phosphatidyl-myo-Inositol Dimannoside Acyltransferase PatA Is Essential for Mycobacterium tuberculosis Growth In Vitro and In Vivo
TLDR
It is determined that PatA, the acyltransferase responsible for the first acylation step of the PIM synthesis pathway, is essential in M. tuberculosis growth in vitro and in vivo and is a novel target for drug discovery programs against this major human pathogen. Expand
Structural basis of phosphatidyl-myo-inositol mannosides biosynthesis in mycobacteria.
TLDR
The structural characterization of the integral membrane phosphatidyl-myo-inositol phosphate synthase (PIPS), and that of three enzymes working at the protein-membrane interface, established the basis of the early steps of the PIM pathway at the molecular level. Expand
Molecular Basis of Membrane Association by the Phosphatidylinositol Mannosyltransferase PimA Enzyme from Mycobacteria*
TLDR
This work determined that PimA preferentially binds to negatively charged phosphatidyl-myo-inositol substrate and non-substrate membrane model systems through its N-terminal domain, inducing an important structural reorganization of anionic phospholipids. Expand
The Molecular Mechanism of Substrate Recognition and Catalysis of the Membrane Acyltransferase PatA from Mycobacteria.
TLDR
The crystal structure of PatA in the presence of 6-O-palmitoyl-α-d-mannopyranoside suggests an inhibitory mechanism for the enzyme, providing exciting possibilities for inhibitor design and the discovery of chemotherapeutic agents against this major human pathogen. Expand
MpbR, an essential transcriptional factor for Mycobacterium tuberculosis survival in the host, modulates PIM biosynthesis and reduces innate immune responses.
TLDR
It is shown that a hypothetical M. tuberculosis transcriptional factor designated as MpbR negatively regulates two transporter genes and affects mycobacterial PIM biosynthesis and biofilm formation and provides new insights into the regulation of myCobacterial lipid metabolism and its correlation with pathogenesis of M.tuber tuberculosis. Expand
Structural basis for selective recognition of acyl chains by the membrane-associated acyltransferase PatA
TLDR
The crystal structures of PatA from Mycobacterium smegmatis are reported, revealing an α/β architecture, with the acyl chain deeply buried into a hydrophobic pocket that runs perpendicular to a long groove where the active site is located. Expand
Therapeutic Potential of the Mycobacterium tuberculosis Mycolic Acid Transporter, MmpL3
TLDR
It is conclusively shown in this study, using conditionally regulated knockdown mutants, that mmpL3 is required for the replication and viability of M. tuberculosis, both under standard laboratory growth conditions and during the acute and chronic phases of infection in mice. Expand
Dissection of membrane-binding and -remodeling regions in two classes of bacterial phospholipid N-methyltransferases.
TLDR
The membrane binding and remodeling capacity of Bradyrhizobium japonicum PmtA and PmtX1 (Rhodobacter-type), which act cooperatively to produce PC in consecutive methylation steps, is investigated and it is proposed that the molecular details of membrane-binding and remodelling are conserved among bacterial Pmts. Expand
Trehalose-6-Phosphate-Mediated Toxicity Determines Essentiality of OtsB2 in Mycobacterium tuberculosis In Vitro and in Mice
TLDR
It is found that otsB2 is essential for growth of M. tuberculosis in vitro as well as for the acute infection phase in mice following aerosol infection and suitable for combination therapies that would minimize the emergence of resistance to OtsB 2 inhibitors. Expand
The Inosine Monophosphate Dehydrogenase, GuaB2, Is a Vulnerable New Bactericidal Drug Target for Tuberculosis
TLDR
In addition to sensitizing Mtb to VCC234718, depletion of GuaB2 was bactericidal in Mtb in vitro and in macrophages, and transcriptional silencing of guaB 2 prevented Mtb from establishing an infection in mice, confirming that Mtb has limited access to guanine in this animal model. Expand
...
1
2
3
...

References

SHOWING 1-10 OF 65 REFERENCES
Molecular Basis of Phosphatidyl-myo-inositol Mannoside Biosynthesis and Regulation in Mycobacteria*
TLDR
Recent advances in the identification of key proteins involved in PIM biogenesis and the determination of the three-dimensional structures of the essential phosphatidyl-myo-inositol mannosyltransferase PimA and the lipoprotein LpqW have led to important insights into the molecular basis of this pathway. Expand
New Insights into the Early Steps of Phosphatidylinositol Mannoside Biosynthesis in Mycobacteria
TLDR
The results support a model wherein Ac1PIM2, a major form of PIMs produced by mycobacteria, arises from the consecutive action of PimA, followed by PimB′, and finally the acyltransferase MSMEG_2934, and the essentiality of these three enzymes emphasizes the interest of novel anti-tuberculosis drugs targeting the initial steps of P IM biosynthesis. Expand
Definition of the First Mannosylation Step in Phosphatidylinositol Mannoside Synthesis
TLDR
It is demonstrated here that the pimA mutant is unable to grow at the higher temperature at which the rescue plasmid is lost, providing the first direct evidence of the essentiality of phosphatidylinositol mannosides for the growth of mycobacteria. Expand
Substrate-induced Conformational Changes in the Essential Peripheral Membrane-associated Mannosyltransferase PimA from Mycobacteria
TLDR
Experimental data support a model wherein the flexibility and conformational transitions confer the adaptability of PimA to the donor and acceptor substrates, which seems to be of importance during catalysis. Expand
Molecular Recognition and Interfacial Catalysis by the Essential Phosphatidylinositol Mannosyltransferase PimA from Mycobacteria*
TLDR
A novel mode of phosphatidylinositol recognition is revealed and this association leads to enzyme activation, providing a template for the development of potential antimycobacterial compounds. Expand
Characterization of a putative alpha-mannosyltransferase involved in phosphatidylinositol trimannoside biosynthesis in Mycobacterium tuberculosis.
Phosphatidyl-myo-inositol mannosides (PIMs), lipomannan (LM) and lipoarabinomannan (LAM) are an important class of bacterial factors termed modulins that are found in tuberculosis and leprosy.Expand
Identification of the Required Acyltransferase Step in the Biosynthesis of the Phosphatidylinositol Mannosides of Mycobacterium Species*
TLDR
Evidence is provided that Rv2611c is the acyltransferase that catalyzes the acyllation of the 6-position of the mannose residue linked to position 2 of myo-inositol in phosphatidylinositols mono- and di-mannosides, and the first evidence that two distinct pathways lead to the formation of acylated PIM2 from PIM1 in mycobacteria. Expand
Inositol lipid metabolism in mycobacteria: biosynthesis and regulatory mechanisms.
TLDR
Current understanding of the inositol lipid metabolism in mycobacteria is summarized and mechanisms that underlie control of LM/LAM glycan polymer elongation are discussed. Expand
Function of Phosphatidylinositol in Mycobacteria*
TLDR
The data suggest that large pools of PI and apolar PIMs are not essential for membrane integrity but are required to sustain polar PIM biosynthesis, which is essential for mycobacterial growth. Expand
Conformational Plasticity of the Essential Membrane-associated Mannosyltransferase PimA from Mycobacteria*
TLDR
This work constitutes the first conformational study of a glycosyl transferase at the single molecule level and proposes a model wherein the conformational transitions are important for the mannosyltransferase to interact with the donor and acceptor substrates/membrane. Expand
...
1
2
3
4
5
...