Mechanisms of ATP to cAMP Conversion Catalyzed by the Mammalian Adenylyl Cyclase: A Role of Magnesium Coordination Shells and Proton Wires.,The Journal of Physical Chemistry B

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Mechanisms of ATP to cAMP Conversion Catalyzed by the Mammalian Adenylyl Cyclase: A Role of Magnesium Coordination Shells and Proton Wires.
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2019-12-27 , DOI: 10.1021/acs.jpcb.9b07349
Bella Grigorenko _{1,

2} , Igor Polyakov _{1,

2} , Alexander Nemukhin _{1,

2}

Affiliation

We report a mechanism of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP) conversion by the mammalian type V adenylyl cyclase revealed in molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) simulations. We characterize a set of computationally derived enzyme-substrate (ES) structures showing an important role of coordination shells of magnesium ions in the solvent accessible active site. In the lowest energy ES conformation, the coordination shell of MgA2+ does not include the Oδ1 atom of the conserved Asp440 residue. Starting from this conformation, a one-step reaction mechanism is characterized that includes proton transfer from the ribose O3'H3' group in ATP to Asp440 via a shuttling water molecule concerted with PA-O3A bond cleavage and O3'-PA bond formation. The energy profile of this route is consistent with the observed reaction kinetics. The computed energy profiles initiated from higher energy ES complexes are characterized by larger energy expenses to complete the reaction. Consistent with experimental data, we show that the Asp440Ala mutant of the enzyme should exhibit a reduced but retained activity. All considered reaction pathways include proton wires from the O3'H3' group via shuttling water molecules.

中文翻译：

哺乳动物腺苷酸环化酶催化ATP转换为cAMP的机制：镁配位壳和质子线的作用。

我们报告了通过分子动力学（MD）和量子力学/分子力学（QM / MM）模拟揭示的哺乳动物V型腺苷酸环化酶将三磷酸腺苷（ATP）转换为环状单磷酸腺苷（cAMP）的机制。我们表征了一组计算得出的酶-底物（ES）结构，这些结构在溶剂可及的活性位点中显示了镁离子配位壳的重要作用。在最低能级ES构象中，MgA2 +的配位壳不包含保守的Asp440残基的Oδ1原子。从该构象开始，特征在于一步反应机理的特征在于包括质子通过与PA-O3A键裂解和O3'-PA键形成协同作用的穿梭水分子从ATP中的核糖O3'H3'基团转移至Asp440。该路线的能量分布与观察到的反应动力学一致。由较高能量的ES配合物引发的计算出的能量分布图的特征在于，为了完成反应需要较大的能量消耗。与实验数据一致，我们表明该酶的Asp440Ala突变体应表现出降低的但保留的活性。所有考虑的反应途径都包括通过穿梭水分子产生的O3'H3'基团的质子线。

更新日期：2020-01-10

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