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Compounds with capacity to quench the tyrosyl radical in Pseudomonas aeruginosa ribonucleotide reductase
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Molecular Biomimetics.ORCID iD: 0000-0002-6717-6612
Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.ORCID iD: 0000-0002-8912-2869
Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden;Swedish Orphan Biovitrum AB, Stockholm, Sweden.
Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.
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2019 (English)In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 24, no 6, p. 841-848Article in journal (Refereed) Published
Abstract [en]

Ribonucleotide reductase (RNR) has been extensively probed as a target enzyme in the search for selective antibiotics. Here we report on the mechanism of inhibition of nine compounds, serving as representative examples of three different inhibitor classes previously identified by us to efficiently inhibit RNR. The interaction between the inhibitors and Pseudomonas aeruginosa RNR was elucidated using a combination of electron paramagnetic resonance spectroscopy and thermal shift analysis. All nine inhibitors were found to efficiently quench the tyrosyl radical present in RNR, required for catalysis. Three different mechanisms of radical quenching were identified, and shown to depend on reduction potential of the assay solution and quaternary structure of the protein complex. These results form a good foundation for further development of P. aeruginosa selective antibiotics. Moreover, this study underscores the complex nature of RNR inhibition and the need for detailed spectroscopic studies to unravel the mechanism of RNR inhibitors.

Place, publisher, year, edition, pages
SPRINGER , 2019. Vol. 24, no 6, p. 841-848
Keywords [en]
Diferric-oxo center, Radicals, Inhibitors, Ribonucleotide reductase, Thermal shift analysis, EPR
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-395703DOI: 10.1007/s00775-019-01679-wISI: 000487094500009PubMedID: 31218442OAI: oai:DiVA.org:uu-395703DiVA, id: diva2:1365046
Funder
Swedish Research Council, 621-2014-5670Swedish Research Council, 2016-01,920Wenner-Gren FoundationsAvailable from: 2019-10-23 Created: 2019-10-23 Last updated: 2019-10-23Bibliographically approved

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