Structural basis for the catalytic mechanism of human phosphodiesterase 9
Structural basis for the catalytic mechanism of human phosphodiesterase 9
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DOI：
10.1073/pnas.0708850105
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发表时间：
2008-09-09
影响因子：
11.1
通讯作者：
Menniti, Frank S.
中科院分区：
文献类型：
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作者：
Liu, Shenping;Mansour, Mahmoud N.;Menniti, Frank S.
磷酸二酯酶(PDE)是一种金属离子依赖的酶，通过代谢失活普遍存在的第二信使cAMP和cGMP来调节细胞信号。在这一角色中，PDE参与了许多生物和代谢过程，并被证明是治疗多种疾病的成功药物的靶标。然而，由于水解反应的速度很快，在原子水平上对PDE的酶机理的实验知识仍然缺乏。在这里，我们报道了在PdE9/晶体中反应稳态积累的反应中间体的结构，并通过冷冻捕获保存。这些结构揭示了PDE的催化过程，并解释了PDE9在实际反应中的底物专一性和PDE的一般阳离子需求。
The phosphodiesterases (PDEs) are metal ion-dependent enzymes that regulate cellular signaling by metabolic inactivation of the ubiquitous second messengers cAMP and cGMP. In this role, the PDEs are involved in many biological and metabolic processes and are proven targets of successful drugs for the treatments of a wide range of diseases. However, because of the rapidity of the hydrolysis reaction, an experimental knowledge of the enzymatic mechanisms of the PDEs at the atomic level is still lacking. Here, we report the structures of reaction intermediates accumulated at the reaction steady state in PDE9/crystal and preserved by freeze-trapping. These structures reveal the catalytic process of a PDE and explain the substrate specificity of PDE9 in an actual reaction and the cation requirements of PDEs in general.