Crystal structures of a bacterial 6-phosphogluconate dehydrogenase reveal aspects of specificity, mechanism and mode of inhibition by analogues of high-energy reaction intermediates

Ramasubramanian Sundaramoorthy, Jorge Iulek, Michael P. Barrett, Olivier Bidet, Gian Filippo Ruda, Ian H. Gilbert, William N. Hunter

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    17 Citations (Scopus)

    Abstract

    Crystal structures of recombinant Lactococcus lactis 6-phosphogluconate dehydrogenase (LlPDH) in complex with substrate, cofactor, product and inhibitors have been determined. LlPDH shares significant sequence identity with the enzymes from sheep liver and the protozoan parasite Trypanosoma brucei for which structures have been reported. Comparisons indicate that the key residues in the active site are highly conserved, as are the interactions with the cofactor and the product ribulose 5-phosphate. However, there are differences in the conformation of the substrate 6-phosphogluconate which may reflect distinct states relevant to catalysis. Analysis of the complex formed with the potent inhibitor 4-phospho-D-erythronohydroxamic acid, suggests that this molecule does indeed mimic the high-energy intermediate state that it was designed to. The analysis also identified, as a contaminant by-product of the inhibitor synthesis, 4-phospho-D-erythronamide, which binds in similar fashion. LlPDH can now serve as a model system for structure-based inhibitor design targeting the enzyme from Trypanosoma species.

    Original languageEnglish
    Pages (from-to)275-286
    Number of pages12
    JournalFEBS Journal
    Volume274
    Issue number1
    DOIs
    Publication statusPublished - Jan 2007

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