Proton-in-Flight Mechanism for the Spontaneous Hydrolysis of N-Methyl O-Phenyl Sulfamate: Implications for the Design of Steroid Sulfatase Inhibitors

The hydrolysis of N-methyl O-phenyl sulfamate (1) has been studied as a model for steroid sulfatase inhibitors such as Coumate, 667 Coumate, and EMATE. At neutral pH, simulating physiological conditions, hydrolysis of 1 involves an intramolecular proton transfer from nitrogen to the bridging oxygen atom of the leaving group. Remarkably, this proton transfer is estimated to accelerate the decomposition of 1 by a factor of 10(11). Examination of existing kinetic data reveals that the sulfatase PaAstA catalyzes the hydrolysis of sulfamate esters with catalytic rate accelerations of similar to 10(4), whereas the catalytic rate acceleration generated by the enzyme for its cognate substrate is on the order of similar to 10(15). Rate constants for hydrolysis of a wide range of sulfuryl esters, ArOSO2X-, are shown to be correlated by a two-parameter equation based on pK(a)(ArOH) and pKa(ArOSO2XH).