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

Lookup NU author(s): Professor Akane KawamuraORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

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. © 2014 Macmillan Publishers Limited. All rights reserved.

Publication metadata

Author(s): Tarhonskaya H, Rydzik AM, Leung IKH, Loik ND, Chan MC, Kawamura A, McCullagh JSO, Claridge TDW, Flashman E, Schofield CJ

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2014

Volume: 5

Online publication date: 05/03/2014

Acceptance date: 10/02/2014

Date deposited: 10/10/2019

ISSN (print): elec-tronic

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/ncomms4423

DOI: 10.1038/ncomms4423

PubMed id: 24594748

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