E. coli Ribonucleotide Reductase β2 Subunit Inactivation by Triapine Occurs through Binding of a Triapine–Fe(II) Adduct,The Journal of Physical Chemistry Letters

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E. coli Ribonucleotide Reductase β2 Subunit Inactivation by Triapine Occurs through Binding of a Triapine–Fe(II) Adduct
The Journal of Physical Chemistry Letters ( IF 4.8 ) Pub Date : 2021-09-13 , DOI: 10.1021/acs.jpclett.1c02103
Mohammad S Safiarian ₁ , R Atlee Watson ₁ , Raquel L Lieberman ₁ , Bridgette A Barry ₁ , Adam R Offenbacher ₂

Affiliation

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 β₂ subunit. Solvent kinetic isotope effects reveal that proton transfer is not rate-limiting for inhibition of Y122· of E. coli RNR β₂ by the pertinent 3AP-Fe(II) adduct. Vibrational spectroscopy further demonstrates that unlike inhibition of the β₂ tyrosyl radical by hydroxyurea, a carboxylate containing proton wire is not at play. Binding measurements reveal a low nanomolar affinity (K_d ∼ 6 nM) of 3AP-Fe(II) for β₂. Taken together, these data should prompt further development of RNR inactivators based on the triapine scaffold for therapeutic applications.

中文翻译：

通过 Triapine-Fe(II) 加合物的结合发生大肠杆菌核糖核苷酸还原酶 β2 亚基失活

核糖核苷酸还原酶 (RNR) 为 DNA 生物合成及其修复提供基础材料，与人类疾病有关，并正在成为治疗靶点。在这里，我们介绍了三苯丙胺 (3AP) 的机理研究，这是一种临床相关的小分子，可抑制 RNR β ₂亚基内的酪氨酰自由基。溶剂动力学同位素效应表明，质子转移不是相关 3AP-Fe(II) 加合物抑制大肠杆菌RNR β ₂的 Y122· 的速率限制。振动光谱进一步证明，与羟基脲对 β ₂酪氨酰基自由基的抑制不同，含有质子线的羧酸盐不起作用。结合测量显示低纳摩尔亲和力 ( K_d ∼ 6 nM) 的 3AP-Fe(II) 用于 β ₂。综上所述，这些数据应该会促进基于三氮平支架的 RNR 灭活剂的进一步开发，用于治疗应用。

更新日期：2021-09-23

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