The rate-determining step in the PTP reaction is hydrolysis of the phosphoenzyme, making kcat independent of the original phosphoester substrate. Members of the PTP superfamily share the same catalytic residues, highly superimposable active site structures, and the same mechanism and transition state for both chemical steps. Yet, their rates vary over several orders of magnitude and exhibit different pH-rate dependencies. For example, at 25 °C, YopH and PTP1B exhibit kcat values for the substrate p-nitrophenyl phosphate (pNPP) of 720 s -1 , and 52 s -1 , respectively, at their pH optima and PTP1B has a significantly broader pH-rate profile than YopH. Other PTP superfamily members such as VHR, VHZ and SsoPTP have lower kcat values of 3 -4 s -1 at 25 °C and pH 5.5. If not active site or mechanistic differences, what, then, gives rise to the highly variable kinetics found among PTPs? In light of recent findings of significant protein dynamics in PTPs, it is likely that differences in loop dynamics play a major role.