Proton-in-flight mechanism for the spontaneous hydrolysis of N-methyl O-phenyl sulfamate: implications for the design of steroid sulfatase inhibitors

J Org Chem. 2012 May 4;77(9):4450-3. doi: 10.1021/jo300386u. Epub 2012 Apr 18.

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).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Arylsulfatases / chemistry*
  • Arylsulfatases / metabolism
  • Catalysis
  • Coumarins / chemistry*
  • Esters
  • Estrone / analogs & derivatives*
  • Estrone / chemistry
  • Hydrogen-Ion Concentration
  • Hydrolysis
  • Kinetics
  • Molecular Structure
  • Steryl-Sulfatase / antagonists & inhibitors*
  • Steryl-Sulfatase / metabolism
  • Sulfonamides / antagonists & inhibitors*
  • Sulfonamides / chemistry*
  • Sulfonic Acids / chemistry*

Substances

  • Coumarins
  • Esters
  • N-methyl-O-phenyl sulfamate
  • Sulfonamides
  • Sulfonic Acids
  • estrone-3-O-sulfamate
  • Estrone
  • irosustat
  • sulfamic acid
  • Arylsulfatases
  • Steryl-Sulfatase