Investigation of a general base mechanism for ester hydrolysis in C-C hydrolase enzymes of the alpha/beta-hydrolase superfamily: a novel mechanism for the serine catalytic triad

Org Biomol Chem. 2007 Feb 7;5(3):507-13. doi: 10.1039/b615605c. Epub 2006 Dec 19.

Abstract

Previous mechanistic and crystallographic studies on two C-C hydrolase enzymes, Escherichia coli MhpC and Burkholderia xenovorans BphD, support a general base mechanism for C-C hydrolytic cleavage, rather than the nucleophilic mechanism expected for a serine hydrolase. The role of the active site serine residue could be to form a hydrogen bond with a gem-diolate intermediate, or to protonate such an intermediate. Hydrolase BphD is able to catalyse the hydrolysis of p-nitrophenyl benzoate ester substrates, which has enabled an investigation of these mechanisms using a Hammett analysis, and comparative studies upon five serine esterases and lipases from the alpha/beta-hydrolase family. A reaction parameter (rho) value of +0.98 was measured for BphD-catalysed ester hydrolysis, implying a build-up of negative charge in the transition state, consistent with a general base mechanism. Values of +0.31-0.61 were measured for other serine esterases and lipases, for the same series of esterase substrates. Pre-steady state kinetic studies of ester hydrolysis, using p-nitrophenyl acetate as the substrate, revealed a single step kinetic mechanism for BphD-catalysed ester hydrolysis, with no burst kinetics. A general base mechanism for BphD-catalysed ester hydrolysis is proposed, in which Ser-112 stabilises an oxyanion intermediate through hydrogen bonding, and assists the rotation of this oxyanion intermediate via proton transfer, a novel reaction mechanism for the serine catalytic triad.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzoates / metabolism
  • Binding Sites
  • Burkholderia / enzymology
  • Catalysis
  • Escherichia coli / enzymology
  • Escherichia coli Proteins / chemistry
  • Escherichia coli Proteins / metabolism
  • Esterases / chemistry
  • Esterases / metabolism
  • Esters / chemistry
  • Esters / metabolism*
  • Hydrogen-Ion Concentration
  • Hydrolases / chemistry
  • Hydrolases / metabolism*
  • Hydrolysis
  • Kinetics
  • Lipase / chemistry
  • Lipase / metabolism
  • Nitrophenols / metabolism
  • Serine / chemistry*
  • Substrate Specificity

Substances

  • Benzoates
  • Escherichia coli Proteins
  • Esters
  • Nitrophenols
  • Serine
  • 4-nitrophenyl acetate
  • Hydrolases
  • Esterases
  • serine esterase
  • Lipase
  • MhpC protein, E coli