Mouse serum paraoxonase-1 lactonase activity is specific for medium-chain length fatty acid lactones.
Recent studies suggest that paraoxonase-1 (PON1), complexed with high-density lipoproteins, is the major lactonase in the circulation. Using 5-hydroxy eicosatetraenoate δ-lactone (5-HETEL) as the substrate, we observed lactonase activity in serum from Pon1-/- mice. However, 6-12 carbon fatty acid γ- and δ-lactones were not hydrolyzed in serum from Pon1-/- mice. Serum from both wild-type and Pon1-/- mice contained a lactonase activity towards 5-HETEL and 3-oxo-dodecanoyl-homoserine lactone that was resistant to inactivation by EDTA. This lactonase activity was sensitive to the serine esterase inhibitor phenyl methyl sulfonyl fluoride and co-eluted with carboxylesterase activity by size-exclusion chromatography. Analysis of serum from the Es1e mouse strain, which has a deficiency in the carboxylesterase, ES-1, proved that this activity was due to ES-1. PON1 activity predominated at early time points (30 s), whereas both PON1 and ES-1 contributed equally at later time points (15 min). When both PON1 and ES-1 were inhibited, 5-HETEL was stable in mouse serum. Thus, while long-chain fatty acid lactones are substrates for PON1, they can be hydrolyzed by ES-1 at neutral pH. In contrast, medium-chain length fatty acid lactones are stable in mouse serum in the absence of PON1, suggesting that PON1 plays a specific role in the metabolism of these compounds.
Department of Medicine, University of Toronto, Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada. connellyp@smh.toronto.on.ca
Philip W
PW
Connelly
Clive M
CM
Picardo
Philip M
PM
Potter
John F
JF
Teiber
Graham F
GF
Maguire
Dominic S
DS
Ng
D000818:Animals; D043303:Aryldialkylphosphatase / Q000097:blood* / Q000235:genetics; D043182:Carboxylesterase / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006868:Hydrolysis; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D007783:Lactones / Q000097:blood* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010664:Phenylmethylsulfonyl Fluoride / Q000494:pharmacology; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D007783:Lactones; D010664:Phenylmethylsulfonyl Fluoride; C047651:5-hydroxyeicosatetraenoic acid lactone; D043182:Carboxylesterase; C469486:Ces1c protein, mouse; D043303:Aryldialkylphosphatase