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Why calcium inhibits magnesium-dependent enzyme phosphoserine phosphatase? A theoretical study

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Abstract

Phosphoserine phosphatase (PSP) utilizes one Mg2+ ion to catalyze the hydrolysis of phospho-l-serine. The displacement of Mg2+ by Ca2+ results in the loss of activity. The reaction mechanisms for the enzyme with both Mg2+ and Ca2+ bound were investigated using hybrid density functional theory. A large quantum chemical model abstracted from the X-ray crystal structure was employed in the calculations. Our calculations shed new insight into the catalytic mechanism of the natural enzyme and its lack of activity by Ca2+ substitution. For the catalytic reaction, our calculations showed that the whole reaction proceeds through two steps, namely dephosphorylation and phosphate hydrolysis. The associated barriers for these two steps are calculated to be 11.9 and 12.0 kcal mol−1, respectively. The Mg-bound Asp11 residue functions as a nucleophile to attack the phosphorus moiety, in concomitant with the departure of the leaving group, which takes a proton from the neutral Asp13 residue. In the subsequent step, the newly formed anionic Asp13 residue activates a water molecule to perform the reverse attack on the phosphoryl intermediate, affording the phosphate product. The substitution of Mg2+ by Ca2+ results in different metal coordination fashion, in which the Asp167 residue changes from bidentate to monodentate and a second water molecule becomes ligated to Ca2+. The calculated barriers for the hydrolysis are ca 8 kcal mol−1 higher than those in the native enzyme, which reconciles with the fact that Ca2+ inhibits the activity of PSP. Several possible reasons are discussed.

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Acknowledgments

We appreciate Dr. Sven de Marothy (from Stockholm University) for providing xyzviewer to create all the figures. This work was supported by grants from the National Natural Science Foundation of China (grant nos. 20733002, 20873008, 21073014, and 21203042), the Fundamental Research Funds for the Central Universities (Grant No. HIT. NSRIF. 2013057), and Major State Basic Research Development Programs (grant nos. 2004CB719903 and 2002CB613406).

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Authors and Affiliations

  1. Institute of Theoretical and Simulation Chemistry, Academy of Fundamental and Interdisciplinary Science, Harbin Institute of Technology, Harbin, 150080, People’s Republic of China

    Ling Yang

  2. College of Chemistry, Beijing Normal University, Beijing, 100875, People’s Republic of China

    Ling Yang, Wan-Jian Ding, Jian-Guo Yu & Ruo-Zhuang Liu

  3. Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470, Mülheim an der Ruhr, Germany

    Rong-Zhen Liao

  4. College of Life Science, Beijing Normal University, Beijing, 100875, People’s Republic of China

    Kai Liu

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Yang, L., Liao, RZ., Ding, WJ. et al. Why calcium inhibits magnesium-dependent enzyme phosphoserine phosphatase? A theoretical study. Theor Chem Acc 131, 1275 (2012). https://doi.org/10.1007/s00214-012-1275-y

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