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Role of HSP90 in the Regulation of de Novo Purine Biosynthesis
Biochemistry ( IF 2.9 ) Pub Date : 2018-03-19 00:00:00 , DOI: 10.1021/acs.biochem.8b00140
Anthony M. Pedley 1 , Georgios I. Karras 2 , Xin Zhang 1 , Susan Lindquist 2, 3, 4 , Stephen J. Benkovic 1
Affiliation  

Despite purines making up one of the largest classes of metabolites in a cell, little is known about the regulatory mechanisms that facilitate efficient purine production. Under conditions resulting in high purine demand, enzymes within the de novo purine biosynthetic pathway cluster into multienzyme assemblies called purinosomes. Purinosome formation has been linked to molecular chaperones HSP70 and HSP90; however, the involvement of these molecular chaperones in purinosome formation remains largely unknown. Here, we present a new-found biochemical mechanism for the regulation of de novo purine biosynthetic enzymes mediated through HSP90. HSP90–client protein interaction assays were employed to identify two enzymes within the de novo purine biosynthetic pathway, PPAT and FGAMS, as client proteins of HSP90. Inhibition of HSP90 by STA9090 abrogated these interactions and resulted in a decrease in the level of available soluble client protein while having no significant effect on their interactions with HSP70. These findings provide a mechanism to explain the dependence of purinosome assembly on HSP90 activity. The combined efforts of molecular chaperones in the maturation of PPAT and FGAMS result in purinosome formation and are likely essential for enhancing the rate of purine production to meet intracellular purine demand.

中文翻译:

在调控HSP90的角色从头嘌呤生物合成

尽管嘌呤构成细胞中最大的代谢产物类别之一,但对于促进有效的嘌呤生产的调控机制知之甚少。在导致高嘌呤需求的条件下,从头嘌呤生物合成途径中的酶会聚集成称为嘌呤体的多酶组装体。嘌呤体的形成与分子伴侣HSP70和HSP90有关。然而,这些分子伴侣在嘌呤体形成中的参与仍然未知。在这里,我们提出了一种新的生化机制,用于调节通过HSP90介导的从头嘌呤嘌呤生物合成酶。使用HSP90-客户蛋白相互作用测定法来从头鉴定两种酶嘌呤的生物合成途径PPAT和FGAMS作为HSP90的客户蛋白质。STA9090对HSP90的抑制作用消除了这些相互作用,并导致可利用的可溶性客户蛋白质水平降低,而对其与HSP70的相互作用没有显着影响。这些发现为解释嘌呤体装配对HSP90活性的依赖性提供了一种机制。分子伴侣在PPAT和FGAMS成熟中的共同努力导致了嘌呤体的形成,并且可能对于提高嘌呤产生的速率以满足细胞内嘌呤的需求至关重要。
更新日期:2018-03-19
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