E. coli Ribonucleotide Reductase ß2 Subunit Inactivation by Triapine Occurs through Binding of a Triapine-Fe(II) Adduct.
J Phys Chem Lett
; 12(37): 9020-9025, 2021 Sep 23.
Article
en En
| MEDLINE
| ID: mdl-34516127
ABSTRACT
Ribonucleotide reductase (RNR), which supplies the building blocks for DNA biosynthesis and its repair, has been linked to human diseases and is emerging as a therapeutic target. Here, we present a mechanistic investigation of triapine (3AP), a clinically relevant small molecule that inhibits the tyrosyl radical within the RNR ß2 subunit. Solvent kinetic isotope effects reveal that proton transfer is not rate-limiting for inhibition of Y122· of E. coli RNR ß2 by the pertinent 3AP-Fe(II) adduct. Vibrational spectroscopy further demonstrates that unlike inhibition of the ß2 tyrosyl radical by hydroxyurea, a carboxylate containing proton wire is not at play. Binding measurements reveal a low nanomolar affinity (Kd â¼ 6 nM) of 3AP-Fe(II) for ß2. Taken together, these data should prompt further development of RNR inactivators based on the triapine scaffold for therapeutic applications.
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Base de datos:
MEDLINE
Asunto principal:
Piridinas
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Ribonucleótido Reductasas
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Tiosemicarbazonas
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Compuestos Ferrosos
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Proteínas de Escherichia coli
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Inhibidores Enzimáticos
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Escherichia coli
Idioma:
En
Revista:
J Phys Chem Lett
Año:
2021
Tipo del documento:
Article