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Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes

A Corrigendum to this article was published on 01 December 2004

Abstract

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 Å. PON1 is a six-bladed β-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.

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Figure 1: Overall structure of PON1.
Figure 2: PON1's active site viewed from above the propeller.
Figure 3: pH-rate profiles of rePON1-G2E6 with 2-naphthyl acetate (2NA, ) and paraoxon ().
Figure 4: The postulated catalytic site and mechanism of PON1.
Figure 5: Sequence alignment of representative members of the PON family.
Figure 6: Proposed model for anchoring of PON1 to the surface of HDL.

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Acknowledgements

We acknowledge financial support by the Minerva Foundation and the Israel Science Foundation to D.S.T. and US army Medical Research & Materiel Command to I.S. and J.L.S. The structure was determined in collaboration with the Israel Structural Proteomics Center, supported by the Israel Ministry of Science & Technology, the European Commission Structural Proteomics Project (SPINE) and the Divadol Foundation. J.L.S. is the Morton and Gladys Pickman Professor of Structural Biology.

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Correspondence to Joel L Sussman or Dan S Tawfik.

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Harel, M., Aharoni, A., Gaidukov, L. et al. Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes. Nat Struct Mol Biol 11, 412–419 (2004). https://doi.org/10.1038/nsmb767

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