Connelly Philip W, Picardo Clive M, Potter Philip M, Teiber John F, Maguire Graham F, Ng Dominic S
Department of Medicine, University of Toronto, Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
Biochim Biophys Acta. 2011 Jan;1811(1):39-45. doi: 10.1016/j.bbalip.2010.10.002. Epub 2010 Oct 29.
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.
最近的研究表明，与高密度脂蛋白结合的对氧磷酶-1（PON1）是循环中的主要内酯酶。以5-羟基二十碳四烯酸δ-内酯（5-HETEL）为底物，我们在Pon1基因敲除小鼠的血清中观察到了内酯酶活性。然而，12碳脂肪酸γ-和δ-内酯在Pon1基因敲除小鼠的血清中未被水解。野生型和Pon1基因敲除小鼠的血清中均含有一种对内切核酸酶耐受的、针对5-HETEL和3-氧代十二烷酰高丝氨酸内酯的内酯酶活性。这种内酯酶活性对丝氨酸酯酶抑制剂苯甲基磺酰氟敏感，并通过尺寸排阻色谱法与羧酸酯酶活性共洗脱。对缺乏羧酸酯酶ES-1的Es1e小鼠品系血清的分析证明，这种活性是由ES-1引起的。PON1活性在早期时间点（30秒）占主导，而在后期时间点（15分钟）PON1和ES-1的贡献相同。当PON1和ES-1均被抑制时，5-HETEL在小鼠血清中保持稳定。因此，虽然长链脂肪酸内酯是PON1的底物，但它们在中性pH条件下可被ES-1水解。相比之下，在没有PON1的情况下，中链长度脂肪酸内酯在小鼠血清中是稳定的，这表明PON1在这些化合物的代谢中起特定作用。
