The straightforward view is that the pH dependency of enzymatic catalysis arises from the pKa values of catalytic residues taking part in the chemical steps. However, the pH dependency can vary between enzymes in the same family even when they share identical catalytic residues due to several factors that cause the kinetic pKa values displayed in a pH-rate profile to be perturbed from their intrinsic, thermodynamic values. For example, differences in the local environment can alter the pKa of catalytic residues. Additionally, the kinetic pKa values reflected in a pH-rate profile are often distorted from the intrinsic, or thermodynamic, pKa values of catalytic residues. For example, we recently showed that a point mutation to a noncatalytic residue in the protein tyrosine phosphatase (PTP) YopH does not significantly affect its maximal turnover number, but broadens its pH-rate dependency, making the variant a much faster enzyme at low pH than the native enzyme. A computational analysis showed this catalytic change arose from mutation-induced changes in conformational equilibria. Point mutations can also alter the pKa of neighboring residues by altering the electrostatic environment, or, by inducing changes in hydrogen bonding and solvation networks. Because of such possibilities the effect on enzymatic catalysis of any mutation is better assessed by assaying rate across a pH range rather than at a single pH. Here, we report findings from a kinetic and computational investigation of point variants of another PTP, SHP-1, that were reported to exhibit faster catalysis than the WT at pH 5. The catalytic activities of PTPs have bell-shaped pH-dependencies and show optimal activity within a narrow range of pH. The bell-shaped pH-rate profiles result from a mechanism that requires specific protonation states of two conserved catalytic residues, an aspartic acid and a cysteine (Figure ). The first step of the PTP mechanism requires the protonated form of the aspartic acid and the deprotonated cysteine nucleophile. Conformational changes of the PTP active site also contribute to activity and the formation of the catalytically competent enzyme-substrate complex (Scheme 1). Classical PTPs exhibit two major conformers that differ in the major orientation of a solvent accessible loop motif, the WPD-loop. In substrate-bound classical PTPs a WPD-loop closed, catalytically active conformation predominates, while in the free enzymes the WPD-loop is primarily found in an open, catalytically nonproductive conformation. Catalysis in PTPs has been correlated with protein motions. In particular, the dynamics of the WPD-loop involving the chemical step, and the variability of these dynamics with pH, can affect the populations of catalytically active enzyme-substrate complexes. Mutations that affect loop equilibrium can alter the pH-rate profile of catalysis in PTPs. 9 The WPD-loop is shown in orange, and the P-loop is shown in green. Reproduced from Ref. with permission from the Royal Society of Chemistry. Originally published under a CC-BY-NC-CD license.