Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities

J Lipid Res. 2005 Jun;46(6):1239-47. doi: 10.1194/jlr.M400511-JLR200. Epub 2005 Mar 16.

Abstract

The paraoxonase (PON) gene family in humans has three members, PON1, PON2, and PON3. Their physiological role(s) and natural substrates are uncertain. We developed a baculovirus-mediated expression system, suitable for all three human PONs, and optimized procedures for their purification. The recombinant PONs are glycosylated with high-mannose-type sugars, which are important for protein stability but are not essential for their enzymatic activities. Enzymatic characterization of the purified PONs has revealed them to be lactonases/lactonizing enzymes, with some overlapping substrates (e.g., aromatic lactones), but also to have distinctive substrate specificities. All three PONs metabolized very efficiently 5-hydroxy-eicosatetraenoic acid 1,5-lactone and 4-hydroxy-docosahexaenoic acid, which are products of both enzymatic and nonenzymatic oxidation of arachidonic acid and docosahexaenoic acid, respectively, and may represent the PONs' endogenous substrates. Organophosphates are hydrolyzed almost exclusively by PON1, whereas bulky drug substrates such as lovastatin and spironolactone are hydrolyzed only by PON3. Of special interest is the ability of the human PONs, especially PON2, to hydrolyze and thereby inactivate N-acyl-homoserine lactones, which are quorum-sensing signals of pathogenic bacteria. None of the recombinant PONs protected low density lipoprotein against copper-induced oxidation in vitro.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aryldialkylphosphatase / physiology*
  • Blotting, Western
  • Cell Line
  • Copper / chemistry
  • Copper / pharmacology
  • Docosahexaenoic Acids / metabolism
  • Electrophoresis, Polyacrylamide Gel
  • Esterases / physiology*
  • Gene Expression Regulation
  • Glycosylation
  • Humans
  • Hydrolysis
  • Hydroxyeicosatetraenoic Acids / metabolism
  • Kinetics
  • Lactones / metabolism*
  • Lipoproteins, LDL / metabolism
  • Liver / metabolism
  • Mannose / chemistry
  • Oxygen / metabolism
  • Recombinant Proteins / chemistry
  • Substrate Specificity
  • Time Factors

Substances

  • Hydroxyeicosatetraenoic Acids
  • Lactones
  • Lipoproteins, LDL
  • Recombinant Proteins
  • Docosahexaenoic Acids
  • 5-hydroxy-6,8,11,14-eicosatetraenoic acid
  • Copper
  • Esterases
  • Aryldialkylphosphatase
  • PON1 protein, human
  • PON2 protein, human
  • PON3 protein, human
  • Mannose
  • Oxygen