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Compounds with capacity to quench the tyrosyl radical in Pseudomonas aeruginosa ribonucleotide reductase
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0002-8912-2869
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Swedish Orphan Biovitrum AB, Sweden.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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Number of Authors: 52019 (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
2019. Vol. 24, no 6, p. 841-848
Keywords [en]
Diferric-oxo center, Radicals, Inhibitors, Ribonucleotide reductase, Thermal shift analysis, EPR
National Category
Biological Sciences Chemical Sciences
Identifiers
URN: urn:nbn:se:su:diva-174949DOI: 10.1007/s00775-019-01679-wISI: 000487094500009PubMedID: 31218442OAI: oai:DiVA.org:su-174949DiVA, id: diva2:1365825
Available from: 2019-10-25 Created: 2019-10-25 Last updated: 2019-10-25Bibliographically approved

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Sahlin, MargaretaSjöberg, Britt-Marie
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