The Evolutionary Origins of Detoxifying Enzymes THE MAMMALIAN SERUM PARAOXONASES (PONs) RELATE TO BACTERIAL HOMOSERINE LACTONASES
The Evolutionary Origins of Detoxifying Enzymes THE MAMMALIAN SERUM PARAOXONASES (PONs) RELATE TO BACTERIAL HOMOSERINE LACTONASES
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DOI：
10.1074/jbc.m112.427922
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发表时间：
2013-08-16
影响因子：
4.8
通讯作者：
Tawfik, Dan S.
中科院分区：
文献类型：
--
作者：
Bar-Rogovsky, Hagit;Hugenmatter, Adrian;Tawfik, Dan S.
血清对氧磷酶（脑桥）是最早在哺乳动物中发现的解毒内酯酶。已知有三个哺乳动物家族，PON 1、2和3，主要存在于肝脏中。它们基本上催化相同的反应，内酯水解，但在底物特异性上不同。虽然一些成员是高度特异性的，但其他成员具有广泛的特异性。因此，脑桥的进化起源和底物特异性仍然知之甚少。在这里，我们报告了一个新发现的细菌脑桥家族，以及三个哺乳动物脑桥家族的祖先的重建。哺乳动物祖先和表征细菌PONX_OCCAL被发现有效地水解N-酰基高丝氨酸内酯，介导在许多细菌，包括致病性的群体感应。因此，哺乳动物的脑桥可能与一个新发现的细菌PON样“群体淬灭”内酯酶家族有关。在后生动物中脑桥的出现可能与先天免疫而不是解毒有关。与细菌PON不同，哺乳动物的祖先也水解，低效率，高丝氨酸内酯以外的内酯，因此之前的解毒功能，后来在三个哺乳动物家族中的两个分歧。哺乳动物祖先的双功能性和群体淬灭和解毒内酯酶活性之间的权衡解释了一些哺乳动物脑桥的广泛和重叠的特异性与其他人的单一特异性。
Serum paraoxonases (PONs) are detoxifying lactonases that were first identified in mammals. Three mammalian families are known, PON1, 2, and 3 that reside primarily in the liver. They catalyze essentially the same reaction, lactone hydrolysis, but differ in their substrate specificity. Although some members are highly specific, others have a broad specificity profile. The evolutionary origins and substrate specificities of PONs therefore remain poorly understood. Here, we report a newly identified family of bacterial PONs, and the reconstruction of the ancestor of the three families of mammalian PONs. Both the mammalian ancestor and the characterized bacterial PONX_OCCAL were found to efficiently hydrolyze N-acyl homoserine lactones that mediate quorum sensing in many bacteria, including pathogenic ones. The mammalian PONs may therefore relate to a newly identified family of bacterial, PON-like "quorum-quenching" lactonases. The appearance of PONs in metazoa is likely to relate to innate immunity rather than detoxification. Unlike the bacterial PON, the mammalian ancestor also hydrolyzes, with low efficiency, lactones other than homoserine lactones, thus preceding the detoxifying functions that diverged later in two of the three mammalian families. The bifunctionality of the mammalian ancestor and the trade-off between the quorum-quenching and detoxifying lactonase activities explain the broad and overlapping specificities of some mammalian PONs versus the singular specificity of others.