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Non-enzymatic chemistry enables 2-hydroxyglutarate-mediated activation of 2-oxoglutarate oxygenases

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Listed:
  • Hanna Tarhonskaya

    (Chemistry Research Laboratory, University of Oxford)

  • Anna M. Rydzik

    (Chemistry Research Laboratory, University of Oxford)

  • Ivanhoe K. H. Leung

    (Chemistry Research Laboratory, University of Oxford)

  • Nikita D. Loik

    (Chemistry Research Laboratory, University of Oxford)

  • Mun Chiang Chan

    (Chemistry Research Laboratory, University of Oxford)

  • Akane Kawamura

    (Chemistry Research Laboratory, University of Oxford)

  • James S. O. McCullagh

    (Chemistry Research Laboratory, University of Oxford)

  • Timothy D. W. Claridge

    (Chemistry Research Laboratory, University of Oxford)

  • Emily Flashman

    (Chemistry Research Laboratory, University of Oxford)

  • Christopher J. Schofield

    (Chemistry Research Laboratory, University of Oxford)

Abstract

Accumulation of (R)-2-hydroxyglutarate in cells results from mutations to isocitrate dehydrogenase that correlate with cancer. A recent study reports that (R)-, but not (S)-2-hydroxyglutarate, acts as a co-substrate for the hypoxia-inducible factor prolyl hydroxylases via enzyme-catalysed oxidation to 2-oxoglutarate. Here we investigate the mechanism of 2-hydroxyglutarate-enabled activation of 2-oxoglutarate oxygenases, including prolyl hydroxylase domain 2, the most important human prolyl hydroxylase isoform. We observe that 2-hydroxyglutarate-enabled catalysis by prolyl hydroxylase domain 2 is not enantiomer-specific and is stimulated by ferrous/ferric ion and reducing agents including L-ascorbate. The results reveal that 2-hydroxyglutarate is oxidized to 2-oxoglutarate non-enzymatically, likely via iron-mediated Fenton-chemistry, at levels supporting in vitro catalysis by 2-oxoglutarate oxygenases. Succinic semialdehyde and succinate are also identified as products of 2-hydroxyglutarate oxidation. Overall, the results rationalize the reported effects of 2-hydroxyglutarate on catalysis by prolyl hydroxylases in vitro and suggest that non-enzymatic 2-hydroxyglutarate oxidation may be of biological interest.

Suggested Citation

  • Hanna Tarhonskaya & Anna M. Rydzik & Ivanhoe K. H. Leung & Nikita D. Loik & Mun Chiang Chan & Akane Kawamura & James S. O. McCullagh & Timothy D. W. Claridge & Emily Flashman & Christopher J. Schofiel, 2014. "Non-enzymatic chemistry enables 2-hydroxyglutarate-mediated activation of 2-oxoglutarate oxygenases," Nature Communications, Nature, vol. 5(1), pages 1-10, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4423
    DOI: 10.1038/ncomms4423
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