title: Proton-in-flight mechanism for the spontaneous hydrolysis of N-methyl O-phenyl sulfamate: implications for the design of steroid sulfatase inhibitors.
abstract: 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 ~10(4), whereas the catalytic rate acceleration generated by the enzyme for its cognate substrate is on the order of ~10(15). Rate constants for hydrolysis of a wide range of sulfuryl esters, ArOSO(2)X(-), are shown to be correlated by a two-parameter equation based on pK(a)(ArOH) and pK(a)(ArOSO2XH).
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Edwards
authors.forename: Richard
authors.initials: R
authors.lastname: Wolfenden
mesh_terms: D001192:Arylsulfatases / Q000737:chemistry* / Q000378:metabolism; D002384:Catalysis; D003374:Coumarins / Q000737:chemistry*; D004952:Esters; D004970:Estrone / Q000031:analogs & derivatives* / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D015394:Molecular Structure; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013451:Sulfonic Acids / Q000737:chemistry*
chemical_list: D003374:Coumarins; D004952:Esters; C575099:N-methyl-O-phenyl sulfamate; D013449:Sulfonamides; D013451:Sulfonic Acids; C088768:estrone-3-O-sulfamate; D004970:Estrone; C520511:irosustat; C005741:sulfamic acid; D001192:Arylsulfatases; D043266:Steryl-Sulfatase