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    Binding mode and selectivity of steroids towards glucose-6-phosphate dehydrogenase from the pathogen Trypanosoma cruzi.

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    Authors
    Ortiz, C
    Moraca, F
    Medeiros, A
    Botta, M
    Hamilton, Niall M
    Comini, M
    Affiliation
    Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Mataojo 2020, Montevideo 11400, Uruguay
    Issue Date
    2016
    
    Metadata
    Show full item record
    Abstract
    Glucose-6-phosphate dehydrogenase (G6PDH) plays a housekeeping role in cell metabolism by generating reducing power (NADPH) and fueling the production of nucleotide precursors (ribose-5-phosphate). Based on its indispensability for pathogenic parasites from the genus Trypanosoma, G6PDH is considered a drug target candidate. Several steroid-like scaffolds were previously reported to target the activity of G6PDH. Epiandrosterone (EA) is an uncompetitive inhibitor of trypanosomal G6PDH for which its binding site to the enzyme remains unknown. Molecular simulation studies with the structure of Trypanosoma cruzi G6PDH revealed that EA binds in a pocket close to the G6P binding-site and protrudes into the active site blocking the interaction between substrates and hence catalysis. Site directed mutagenesis revealed the important steroid-stabilizing effect of residues (L80, K83 and K84) located on helix α-1 of T. cruzi G6PDH. The higher affinity and potency of 16α-Br EA by T. cruzi G6PDH is explained by the formation of a halogen bond with the hydrogen from the terminal amide of the NADP+-nicotinamide. At variance with the human enzyme, the inclusion of a 21-hydroxypregnane-20-one moiety to a 3β-substituted steroid is detrimental for T. cruzi G6PDH inhibition. The species-specificity of certain steroid derivatives towards the parasite G6PDH and the corresponding biochemically validated binding models disclosed in this work may prove valuable for the development of selective inhibitors against the pathogen's enzyme.
    Citation
    Binding Mode and Selectivity of Steroids towards Glucose-6-phosphate Dehydrogenase from the Pathogen Trypanosoma cruzi. 2016, 21 (3): Molecules
    Journal
    Molecules
    URI
    http://hdl.handle.net/10541/606642
    DOI
    10.3390/molecules21030368
    PubMed ID
    26999093
    Type
    Article
    Language
    en
    ISSN
    1420-3049
    ae974a485f413a2113503eed53cd6c53
    10.3390/molecules21030368
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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