The nucleoside inosine is a main intermediate of purine nucleotide catabolism in Saccharomyces cerevisiae and is produced via the dephosphorylation of inosine monophosphate (IMP) by IMP-specific 5′-nucleotidase 1 (ISN1), which is present in many eukaryotic organisms. Upon transition of yeast from oxidative to fermentative growth, ISN1 is important for intermediate inosine accumulation as purine storage, but details of ISN1 regulation are unknown. We characterized structural and kinetic behavior of ISN1 from S. cerevisiae (ScISN1) and showed that tetrameric ScISN1 is negatively regulated by inosine and adenosine triphosphate (ATP). Regulation involves an inosine-binding allosteric site along with IMP-induced local and global conformational changes in the monomer and a tetrameric re-arrangement, respectively. A proposed interaction network propagates local conformational changes in the active site to the intersubunit interface, modulating the allosteric features of ScISN1. Via ATP and inosine, ScISN1 activity is likely fine-tuned to regulate IMP and inosine homeostasis. These regulatory and catalytic features of ScISN1 contrast with those of the structurally homologous ISN1 from Plasmodium falciparum, indicating that ISN1 enzymes may serve different biological purposes in different organisms.

中文翻译：

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酿酒酵母肌苷 5'-单磷酸特异性磷酸酶的结构、协同作用和抑制作用

核苷肌苷是酿酒酵母中嘌呤核苷酸分解代谢的主要中间体，是通过 IMP 特异性 5'-核苷酸酶 1 (ISN1) 对肌苷单磷酸 (IMP) 去磷酸化产生的，ISN1 存在于许多真核生物中。当酵母从氧化生长转变为发酵生长时，ISN1 对于作为嘌呤储存的中间肌苷积累非常重要，但 ISN1 调节的细节尚不清楚。我们对酿酒酵母ISN1 (ScISN1) 的结构和动力学行为进行了表征，并表明四聚体 ScISN1 受到肌苷和三磷酸腺苷 (ATP) 的负调节。调节涉及肌苷结合变构位点以及 IMP 分别诱导的单体和四聚体重排的局部和整体构象变化。所提出的相互作用网络将活性位点的局部构象变化传播到亚基间界面，调节 ScISN1 的变构特征。通过 ATP 和肌苷，ScISN1 活性可能会进行微调以调节 IMP 和肌苷稳态。ScISN1 的这些调节和催化特征与恶性疟原虫中结构同源的 ISN1 的调节和催化特征形成鲜明对比，表明 ISN1 酶可能在不同的生物体中发挥不同的生物学作用。