Paraoxonases-1, -2 and -3: What are their functions?
Paraoxonases-1, -2 and -3: What are their functions?
复制标题
DOI：
10.1016/j.cbi.2016.05.036
复制
发表时间：
2016-11-25
影响因子：
5.1
通讯作者：
Costa LG
中科院分区：
文献类型：
--
作者：
Furlong CE;Marsillach J;Jarvik GP;Costa LG
对氧磷酶-1 (PON1) 是一种主要与血浆高密度脂蛋白 (HDL) 相关的酯酶/内酯酶，是该酶家族中第一个被表征的成员。它的名字来源于它水解对氧磷的能力，对氧磷是杀虫剂对硫磷的有毒代谢物。相关酶PON2和PON3因其与PON1的进化关系而被命名。每个 PON 基因都被敲除的小鼠是在加州大学洛杉矶分校培育的，对于阐明它们在有机磷 (OP) 代谢、心血管疾病、先天免疫、肥胖和癌症中的作用至关重要。通过两种底物分析确定的 PON1 状态揭示了个体的功能性 Q192R 基因型和活动水平。嵌合 PON1 的三维结构对于理解 PON1 的结构特性以及将 PON1 设计为 OP 化合物的催化清除剂非常有用。所有三种 PON 都会水解微生物 N-酰基高丝氨酸内酯群体感应因子，从而抑制铜绿假单胞菌的发病机制。所有三种 PON 均可调节氧化应激和炎症。 PON2 定位于线粒体和内质网。 PON2 具有有效的抗氧化特性，雌性小鼠中的 PON2 水平比雄性小鼠高 3 至 4 倍，可以增强对氧化应激的保护，正如在雌性小鼠神经元和星形胶质细胞原代培养物中观察到的，与雄性小鼠相比。女性中 PON2 水平较高，这可能解释了女性患神经系统和心血管疾病的频率较低，以及使用特殊的 PON1 状态测定来识别男性而非女性患有帕金森病的能力。对 PON3 知之甚少；然而，最近对 PON3 基因敲除小鼠进行的实验表明，它们容易肥胖、形成胆结石和动脉粥样硬化。与 PON 1 和 2 一样，PON3 似乎也能调节氧化应激。它定位在内质网、线粒体和高密度脂蛋白上。 PON2 和 PON3 在癌症中均上调，通过线粒体保护免受氧化应激和细胞凋亡促进肿瘤进展。
Paraoxonase-1 (PON1), an esterase/lactonase primarily associated with plasma high-density lipoprotein (HDL), was the first member of this family of enzymes to be characterized. Its name was derived from its ability to hydrolyze paraoxon, the toxic metabolite of the insecticide parathion. Related enzymes PON2 and PON3 were named from their evolutionary relationship with PON1. Mice with each PON gene knocked out were generated at UCLA and have been key for elucidating their roles in organophosphorus (OP) metabolism, cardiovascular disease, innate immunity, obesity, and cancer. PON1 status, determined with two-substrate analyses, reveals an individual’s functional Q192R genotype and activity levels. The three-dimensional structure for a chimeric PON1 has been useful for understanding the structural properties of PON1 and for engineering PON1 as a catalytic scavenger of OP compounds. All three PONs hydrolyze microbial N-acyl homoserine lactone quorum sensing factors, quenching Pseudomonas aeruginosa’s pathogenesis. All three PONs modulate oxidative stress and inflammation. PON2 is localized in the mitochondria and endoplasmic reticulum. PON2 has potent antioxidant properties and is found at 3- to 4-fold higher levels in females than males, providing increased protection against oxidative stress, as observed in primary cultures of neurons and astrocytes from female mice compared with male mice. The higher levels of PON2 in females may explain the lower frequency of neurological and cardiovascular diseases in females and the ability to identify males but not females with Parkinson’s disease using a special PON1 status assay. Less is known about PON3; however, recent experiments with PON3 knockout mice show them to be susceptible to obesity, gallstone formation and atherosclerosis. Like PONs 1 and 2, PON3 also appears to modulate oxidative stress. It is localized in the endoplasmic reticulum, mitochondria and on HDL. Both PON2 and PON3 are upregulated in cancer, favoring tumor progression through mitochondrial protection against oxidative stress and apoptosis.