Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes
Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes
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DOI：
10.1038/nsmb767
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发表时间：
2004-05-01
影响因子：
16.8
通讯作者：
Tawfik, DS
中科院分区：
文献类型：
--
作者：
Harel, M;Aharoni, A;Tawfik, DS
血清对氧磷酶（PON）家族的成员已在哺乳动物和其他脊椎动物以及无脊椎动物中鉴定。脑桥具有广泛的生理活性，包括药物代谢和神经毒剂的解毒。PON1和PON3位于高密度脂蛋白（HDL，好胆固醇）上，并参与动脉粥样硬化的预防。我们描述了PON家族成员的第一个晶体结构，通过定向进化获得的PON 1的变体，分辨率为2.2埃。PON1是一个六叶β螺旋桨，具有独特的活性位点盖子，也参与HDL结合。三维结构和定向进化研究允许详细描述PON 1的活性位点和催化机制，这让人联想到分泌型磷脂酶A2，PON家族成员的路线，朝着不同的底物和反应选择性分歧。
Members of the serum paraoxonase (PON) family have been identified in mammals and other vertebrates, and in invertebrates. PONs exhibit a wide range of physiologically important hydrolytic activities, including drug metabolism and detoxification of nerve agents. PON1 and PON3 reside on high-density lipoprotein (HDL, good cholesterol) and are involved in the prevention of atherosclerosis. We describe the first crystal structure of a PON family member, a variant of PON1 obtained by directed evolution, at a resolution of 2.2 Angstrom. PON1 is a six-bladed beta-propeller with a unique active site lid that is also involved in HDL binding. The three-dimensional structure and directed evolution studies permit a detailed description of PON1's active site and catalytic mechanism, which are reminiscent of secreted phospholipase A2, and of the routes by which PON family members diverged toward different substrate and reaction selectivities.