title: Lactonase and lactonizing activities of human serum paraoxonase (PON1) and rabbit serum PON3.
abstract: Human paraoxonase (PON1) was previously shown to hydrolyze over 30 different lactones (cyclic esters). In the present study purified human PON1 was found to catalyze the reverse reaction (lactonization) of a broad range of hydroxy acids. Hydroxy acid lactonization or lactone hydrolysis is catalyzed until equilibrium between the open and closed forms is reached. Lactonization by PON1 was calcium-dependent, had a pH optimum of 5.5-6 and could be stimulated with dilauroylphosphatidylcholine. Rabbit serum PON3 and a serine esterase in mouse plasma, presumably a carboxylesterase, also catalyzed hydroxy acid lactonization. Two endogenous oxidized unsaturated fatty acids, (+/-)4-hydroxy-5E,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid (4-HDoHE) and (+/-)5-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-HETE) lactone, were very efficiently lactonized and hydrolyzed, respectively, by PON1. Human and mouse plasma samples also catalyzed 4-HDoHE lactonization and 5-HETE lactone hydrolysis. Studies with the PON1 inhibitor EDTA and the serine esterase inhibitor phenylmethylsulfonylfluoride suggest that about 80-95% of both activities can be attributed to PON1 in the human samples. In the mouse sample, PON1 accounted for about 30% of the 4-HDoHE lactonizing activity and 72% of the 5-HETE lactonase activity. Our results demonstrate that PON1 can lactonize the hydroxy acid form of its lactone substrates and that reversible hydrolysis of lactones may be a property of lactonases that is not generally considered. Also, the high activity of PON1 towards 4-HDoHE and 5-HETE lactone suggests that oxidized eicosanoids and docosanoids may be important physiological substrates for PON1.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Teiber
authors.forename: Dragomir I
authors.initials: DI
authors.lastname: Draganov
authors.forename: Bert N
authors.initials: BN
authors.lastname: La Du
mesh_terms: D000818:Animals; D043303:Aryldialkylphosphatase; D004950:Esterases / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D007783:Lactones / Q000378:metabolism*; D008148:Lovastatin / Q000378:metabolism; D051379:Mice; D011817:Rabbits; D019821:Simvastatin / Q000378:metabolism; D013045:Species Specificity; D013379:Substrate Specificity
chemical_list: D005227:Fatty Acids; D007783:Lactones; D008148:Lovastatin; D019821:Simvastatin; D004950:Esterases; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; C113656:PON3 protein, human