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Chemistry. 2018 Apr 6;24(20):5225-5237. doi: 10.1002/chem.201704617. Epub 2018 Jan 11.

On the Structure and Reaction Mechanism of Human Acireductone Dioxygenase.

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Jerzy Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Niezapominajek 8, 30-239, Krakow, Poland.
University of Virginia, Department of Molecular Physiology and Biological Physics, 1340 Jefferson Park Avenue, Charlottesville, VA, 22908, USA.
University of South Carolina, Department of Chemistry and Biochemistry, 631 Sumter Street, Columbia, SC, 29208, USA.
National Synchrotron Radiation Centre Solaris, Jagiellonian University, ul. Czerwone Maki 98, 30-392, Kraków, Poland.
AGH University of Science and Technology, Faculty of Physics and Applied Computer Science, al. Mickiewicza 30, 30-059, Kraków, Poland.
European Synchrotron Radiation Facility (ESRF), P.O. Box 220, F-, 38043, Grenoble, France.
Jagiellonian University, Faculty of Chemistry, ul. Romana Ingardena 3, 30-060, Kraków, Poland.
Department of Physical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland.
Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387, Krakow, Poland.


Acireductone dioxygenase (ARD) is an intriguing enzyme from the methionine salvage pathway that is capable of catalysing two different oxidation reactions with the same substrate depending on the type of the metal ion in the active site. To date, the structural information regarding the ARD-acireductone complex is limited and possible reaction mechanisms are still under debate. The results of joint experimental and computational studies undertaken to advance knowledge about ARD are reported. The crystal structure of an ARD from Homo sapiens was determined with selenomethionine. EPR spectroscopy suggested that binding acireductone triggers one protein residue to dissociate from Fe2+ , which allows NO (and presumably O2 ) to bind directly to the metal. Mössbauer spectroscopic data (interpreted with the aid of DFT calculations) was consistent with bidentate binding of acireductone to Fe2+ and concomitant dissociation of His88 from the metal. Major features of Fe vibrational spectra obtained for the native enzyme and upon addition of acireductone were reproduced by QM/MM calculations for the proposed models. A computational (QM/MM) study of the reaction mechanisms suggests that Fe2+ promotes O-O bond homolysis, which elicits cleavage of the C1-C2 bond of the substrate. Higher M3+ /M2+ redox potentials of other divalent metals do not support this pathway, and instead the reaction proceeds similarly to the key reaction step in the quercetin 2,3-dioxygenase mechanism.


EPR spectroscopy; Mössbauer spectroscopy; acireductone dioxygenase; protein structures; reaction mechanisms


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