Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes
Top Cited Papers
- 18 April 2004
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Structural & Molecular Biology
- Vol. 11 (5), 412-419
- https://doi.org/10.1038/nsmb767
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.Keywords
This publication has 36 references indexed in Scilit:
- Pharmacogenetics of paraoxonases: a brief reviewNaunyn-Schmiedebergs Archiv für experimentelle Pathologie und Pharmakologie, 2004
- High density lipoprotein structureFrontiers in Bioscience-Landmark, 2003
- Oxidative stress increases the expression of the CD36 scavenger receptor and the cellular uptake of oxidized low-density lipoprotein in macrophages from atherosclerotic mice: protective role of antioxidants and of paraoxonaseAtherosclerosis, 2002
- Human Paraoxonase-3 Is an HDL-Associated Enzyme With Biological Activity Similar to Paraoxonase-1 Protein but Is Not Regulated by Oxidized LipidsArteriosclerosis, Thrombosis, and Vascular Biology, 2001
- Hydrolysis of platelet-activating factor by human serum paraoxonaseBiochemical Journal, 2001
- Apolipoprotein A-I Promotes the Formation of Phosphatidylcholine Core Aldehydes That Are Hydrolyzed by Paraoxonase (PON-1) during High Density Lipoprotein Oxidation with a Peroxynitrite DonorJournal of Biological Chemistry, 2001
- AtherosclerosisNature, 2000
- Calcium-dependent Human Serum Homocysteine Thiolactone HydrolasePublished by Elsevier BV ,2000
- Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosisNature, 1998
- Paraoxonase prevents accumulation of lipoperoxides in low‐density lipoproteinFEBS Letters, 1991