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

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 () and Christopher J. Schofield ()
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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

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4423

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