Inhibition of chicken liver carboxylesterase by activated carbonyls and carbonyl hydrates

Biochim Biophys Acta. 1996 Dec 5;1298(2):159-66. doi: 10.1016/s0167-4838(96)00117-3.

Abstract

Identical Kcat values (approximately 40 s-1) are obtained for the chicken liver carboxylesterase catalyzed hydrolysis of phenyl, p-nitrophenyl and o-nitrophenyl benzoates providing support for the involvement of an acyl-enzyme pathway, with the rate-limiting deacylation of a common benzoyl-enzyme intermediate. Chicken liver carboxylesterase catalyzed fragmentation of (E)-benzilmonoxime O-2,4-dinitrophenyl ether shows a pH dependence on a group active in the free base form with a pK'a approximately 5.0. The Ki-pH profile for benzil inhibition shows a dependence on a similar group with a pK'a = 5.4. The reactions between chicken liver carboxylesterase and the hydrated aldehyde, chloral hydrate, have shown this compound to be at once a substrate and potent inhibitor of the enzyme. The kinetics of inhibition are consistent with a mechanism in which the bound hydrate is first dehydrated in a rate-limiting step catalyzed by the enzyme. Nucleophilic attack by the active-site serine on the parent aldehyde produces a hemiacetal adduct. The Ki value for chloral hydrate inhibition calculated from the kinetic analysis (90 nM) compares favourably with the value measured from the steady-state kinetics (87 nM).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoates / chemistry
  • Carboxylesterase
  • Carboxylic Ester Hydrolases / antagonists & inhibitors*
  • Catalysis
  • Chickens
  • Chloral Hydrate / chemistry*
  • Dinitrobenzenes / chemistry
  • Enzyme Activation
  • Enzyme Inhibitors / chemistry*
  • Esters / chemistry
  • Hydrogen-Ion Concentration
  • Hydrolysis
  • Liver / enzymology

Substances

  • Benzoates
  • Dinitrobenzenes
  • Enzyme Inhibitors
  • Esters
  • Chloral Hydrate
  • Carboxylic Ester Hydrolases
  • Carboxylesterase