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• W2150051736 endingPage "e1001599" @default.
• W2150051736 startingPage "e1001599" @default.
• W2150051736 abstract "Enzymes stabilize transition states of reactions while limiting binding to ground states, as is generally required for any catalyst. Alkaline Phosphatase (AP) and other nonspecific phosphatases are some of Nature's most impressive catalysts, achieving preferential transition state over ground state stabilization of more than 1022-fold while utilizing interactions with only the five atoms attached to the transferred phosphorus. We tested a model that AP achieves a portion of this preference by destabilizing ground state binding via charge repulsion between the anionic active site nucleophile, Ser102, and the negatively charged phosphate monoester substrate. Removal of the Ser102 alkoxide by mutation to glycine or alanine increases the observed Pi affinity by orders of magnitude at pH 8.0. To allow precise and quantitative comparisons, the ionic form of bound Pi was determined from pH dependencies of the binding of Pi and tungstate, a Pi analog lacking titratable protons over the pH range of 5–11, and from the 31P chemical shift of bound Pi. The results show that the Pi trianion binds with an exceptionally strong femtomolar affinity in the absence of Ser102, show that its binding is destabilized by ≥108-fold by the Ser102 alkoxide, and provide direct evidence for ground state destabilization. Comparisons of X-ray crystal structures of AP with and without Ser102 reveal the same active site and Pi binding geometry upon removal of Ser102, suggesting that the destabilization does not result from a major structural rearrangement upon mutation of Ser102. Analogous Pi binding measurements with a protein tyrosine phosphatase suggest the generality of this ground state destabilization mechanism. Our results have uncovered an important contribution of anionic nucleophiles to phosphoryl transfer catalysis via ground state electrostatic destabilization and an enormous capacity of the AP active site for specific and strong recognition of the phosphoryl group in the transition state." @default.
• W2150051736 created "2016-06-24" @default.
• W2150051736 creator A5052907425 @default.
• W2150051736 creator A5061507169 @default.
• W2150051736 creator A5076625801 @default.
• W2150051736 date "2013-07-02" @default.
• W2150051736 modified "2023-10-11" @default.
• W2150051736 title "Ground State Destabilization by Anionic Nucleophiles Contributes to the Activity of Phosphoryl Transfer Enzymes" @default.
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• W2150051736 doi "https://doi.org/10.1371/journal.pbio.1001599" @default.
• W2150051736 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3699461" @default.
• W2150051736 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/23843744" @default.
• W2150051736 hasPublicationYear "2013" @default.
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• W2150051736 hasAuthorship W2150051736A5052907425 @default.
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