Research Guides

Professor 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-degron 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 use our structural and functional understanding of these enzymes to identify ways to modulate their activity through chemical and genetic engineering, as well as to understand how the redox environment of the cell impacts these processes.  Ultimately we seek to find ways to engineer plants to improve their survival of flood events. This type of engineering could help make crops more tolerant of climate extremes. 

We are also interested more broadly in the role of thiol dioxygenases in oxygen sensing and how this has evolved across kingdoms. Not only are thiol dioxygenases present in algae, but they also play a role in oxygen-sensing in humans. ADO is a human thiol dioxygenases which catalyses oxidation of Nt-Cys residues on target proteins to CSA, thus targeting them for degradation by the N-degron pathway in an oxygen sensitive manner. Modulation of the activity of ADO could therefore contribute to managing the response to hypoxia, a feature of many diseases.

 

 

Hammarlund EU, Flashman E, Mohlin S, Licausi F (2020). Oxygen-sensing mechanisms across eukaryotic kingdoms and their roles in complex multicellularity. Science. 370(6515) eaba3512.

White MD, Dalle Carbonare L, Lavilla Puerta M, Iacopino S, Edwards M, Dunne K, Pires E, Levy C, McDonough MA, Licausi F, Flashman E (2020). Structures of Arabidopsis thaliana oxygen-sensing plant cysteine oxidases 4 and 5 enable targeted manipulation of their activity. Proc Natl Acad Sci U S A. 117:23140. 

Masson N, Keeley TP, Giuntoli B, White MD, Puerta ML, Perata P, Flashman E, Licausi F, Ratcliffe PJ (2019). Conserved N-terminal cysteine dioxygenases transduce responses to hypoxia in animals and plants. Science. 365:65.      

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.

 

For a full publication list see my PubMed profile.

 

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