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Structural Insights into the Forward and Reverse Enzymatic Reactions in Human Adenine Phosphoribosyltransferase
Cell Chemical Biology ( IF 8.6 ) Pub Date : 2018-03-22 , DOI: 10.1016/j.chembiol.2018.02.011
Jessica Huyet , Mohammad Ozeir , Marie-Claude Burgevin , Benoît Pinson , Françoise Chesney , Jean-Marc Remy , Abdul Rauf Siddiqi , Roland Lupoli , Gregory Pinon , Christelle Saint-Marc , Jean-Francois Gibert , Renaud Morales , Irène Ceballos-Picot , Robert Barouki , Bertrand Daignan-Fornier , Anne Olivier-Bandini , Franck Augé , Pierre Nioche

Phosphoribosyltransferases catalyze the displacement of a PRPP α-1′-pyrophosphate to a nitrogen-containing nucleobase. How they control the balance of substrates/products binding and activities is poorly understood. Here, we investigated the human adenine phosphoribosyltransferase (hAPRT) that produces AMP in the purine salvage pathway. We show that a single oxygen atom from the Tyr105 side chain is responsible for selecting the active conformation of the 12 amino acid long catalytic loop. Usingin vitro, cellular, andin crystalloapproaches, we demonstrated that Tyr105 is key for the fine-tuning of the kinetic activity efficiencies of the forward and reverse reactions. Together, our results reveal an evolutionary pressure on the strictly conserved Tyr105 and on the dynamic motion of the flexible loop in phosphoribosyltransferases that is essential for purine biosynthesis in cells. These data also provide the framework for designing novel adenine derivatives that could modulate, through hAPRT, diseases-involved cellular pathways.

中文翻译:

在人类腺嘌呤磷酸核糖基转移酶中的正向和反向酶促反应的结构见解。

磷酸核糖基转移酶催化PRPPα-1'-焦磷酸置换为含氮核碱基。他们如何控制底物/产品结合和活性之间的平衡知之甚少。在这里,我们调查了在嘌呤挽救途径中产生AMP的人腺嘌呤磷酸核糖基转移酶(hAPRT)。我们显示,一个来自Tyr105侧链的氧原子负责选择12个氨基酸长的催化环的活性构象。使用体外,细胞和晶体学方法,我们证明了Tyr105是微调正向和反向反应动力学活性的关键。一起,我们的研究结果揭示了严格保守的Tyr105和磷酸核糖基转移酶中柔性环动态运动的进化压力,这对于细胞中嘌呤的生物合成至关重要。这些数据也为设计新型腺嘌呤衍生物提供了框架,该腺嘌呤衍生物可通过hAPRT调节疾病相关的细胞途径。
更新日期:2018-06-22
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