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  • Probing function and structure of trehalose-6-phosphate phosphatases from pathogenic organisms suggests distinct molecular groupings

    Author(s)
    Cross, Megan
    Lepage, Romain
    Rajan, Siji
    Biberacher, Sonja
    Young, Neil D
    Kim, Bo-Na
    Coster, Mark J
    Gasser, Robin B
    Kim, Jeong-Sun
    Hofmann, Andreas
    Griffith University Author(s)
    Coster, Mark J.
    Hofmann, Andreas
    Lepage, Romain
    Cross, Megan O.
    Biberacher, Sonja M.
    Rajan, Siji
    Year published
    2017
    Metadata
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    Abstract
    The trehalose biosynthetic pathway is of great interest for the development of novel therapeutics because trehalose is an essential disaccharide in many pathogens but is neither required nor synthesized in mammalian hosts. As such, trehalose-6-phosphate phosphatase (TPP), a key enzyme in trehalose biosynthesis, is likely an attractive target for novel chemotherapeutics. Based on a survey of genomes from a panel of parasitic nematodes and bacterial organisms and by way of a structure-based amino acid sequence alignment, we derive the topological structure of monoenzyme TPPs and classify them into 3 groups. Comparison of the ...
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    The trehalose biosynthetic pathway is of great interest for the development of novel therapeutics because trehalose is an essential disaccharide in many pathogens but is neither required nor synthesized in mammalian hosts. As such, trehalose-6-phosphate phosphatase (TPP), a key enzyme in trehalose biosynthesis, is likely an attractive target for novel chemotherapeutics. Based on a survey of genomes from a panel of parasitic nematodes and bacterial organisms and by way of a structure-based amino acid sequence alignment, we derive the topological structure of monoenzyme TPPs and classify them into 3 groups. Comparison of the functional roles of amino acid residues located in the active site for TPPs belonging to different groups reveal nuanced variations. Because current literature on this enzyme family shows a tendency to infer functional roles for individual amino acid residues, we investigated the roles of the strictly conserved aspartate tetrad in TPPs of the nematode Brugia malayi by using a conservative mutation approach. In contrast to aspartate-213, the residue inferred to carry out the nucleophilic attack on the substrate, we found that aspartate-215 and aspartate-428 of BmTPP are involved in the chemistry steps of enzymatic hydrolysis of the substrate. Therefore, we suggest that homology-based inference of functionally important amino acids by sequence comparison for monoenzyme TPPs should only be carried out for each of the 3 groups.
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    Journal Title
    FASEB Journal
    DOI
    https://doi.org/10.1096/fj.201601149R
    Note
    This publication has been entered into Griffith Research Online as an Advanced Online Version.
    Subject
    Biochemistry and cell biology
    Zoology
    Medical parasitology
    Medical physiology
    Publication URI
    http://hdl.handle.net/10072/100927
    Collection
    • Journal articles

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