Research Guides

Department of Chemistry University of Oxford

Dr Emily Flashman

Enzyme-Mediated Responses to Low Oxygen Stress

All aerobic organisms must balance oxygen supply and demand, and therefore need response systems when oxygen availability drops (hypoxia) to allow adaptation to hypoxic conditions. These adaptations might include mechanisms to deliver more oxygen, or conversely metabolic reconfiguration to use less oxygen. In plants and animals, these responses are mediated by transcription factors that upregulate genes to enable the hypoxic response, and these transcription factors are in turn regulated by oxygen-dependent enzymes. Thus under normal oxygen conditions, the enzymes catalyse post-translational modification of the transcription factors targetting them for degradation by the proteasome, while in hypoxia the enzymes lose catalytic activity and the transcription factors are stabilised to elicit the hypoxic response.

In plants the hypoxic response is mediated by Group VII Ethylene Response Factors (ERF-VIIs), whose levels are regulated by the catalytic activity of Plant Cysteine Oxidases. We have reported that Plant Cysteine Oxidases (PCOs) catalyse ERF-VII Nt-Cys oxidation to Cys-sulfinic acid (CSA), and that this is necessary and sufficient to trigger their degradation by the N-end rule pathway. We have also shown that their activity is sensitive to oxygen availability. The PCOs therefore directly connect environmental stress (flood-induced hypoxia) and the subsequent biological adaptation. We are interested in modulating PCO activity as a way to stabilise ERF-VII transcription factors, which could result in improved survival of flood events. This type of engineering could help make crops more tolerant of climate extremes. 

 

Gibbs DJ, Tedds HM, Labandera AM, Bailey M, White MD, Hartman S, Sprigg C, Mogg SL, Osborne R, Dambire C, Boeckx T, Paling Z, Voesenek LACJ, Flashman E, Holdsworth MJ (2018). Oxygen-dependent proteolysis regulates the stability of angiosperm polycomb repressive complex 2 subunit VERNALIZATION 2. Nat Commun9: 5438. 

White MD, Kamps JJAG, East S, Taylor Kearney LJ, Flashman E (2018). The plant cysteine oxidases from Arabidopsis thaliana are kinetically tailored to act as oxygen sensors. J Biol Chem. 293: 11786-11795.

White MD, Klecker M, Hopkinson RJ, Weits DA, Mueller C, Naumann C, O'Neill R, Wickens J, Yang J, Brooks-Bartlett JC, Garman EF, Grossmann TN, Dissmeyer N, Flashman E (2017). Plant cysteine oxidases are dioxygenases that directly enable arginyl transferase-catalysed arginylation of N-end rule targets. Nat Commun. 8: 14690.

Foskolou IP, Jorgensen C, Leszczynska KB, Olcina MM, Tarhonskaya H, Haisma B, D'Angiolella V, Myers WK, Domene C, Flashman E, Hammond EM (2017). Ribonucleotide reductase requires subunit switching in hypoxia to maintain DNA replication. Mol Cell. 66: 206-220.

Hancock RL, Masson N, Dunne K, Flashman E, Kawamura A (2017). The activity of JmjC histone demethylase KDM4A is highly sensitive to oxygen concentrations. ACS Chem Biol12: 1011-1019

White MD and Flashman E (2016). Catalytic strategies of the non-heme iron dependent oxygenases and their roles in plant biology. Curr Opin Chem Biol.31: 126-135.

 

For a full publication list see my PubMed profile.