Characterization of the PON1 active site using modeling simulation, in relation to PON1 lactonase activity.
Paraoxonase1 (PON1) is a HDL bound enzyme and many of the anti-atherogenic properties of HDL are attributed to PON1. The enzyme precise mechanism of protective action and its endogenous substrate remain elusive. PON1 hydrolyzes organophosphates, arylesters and lactones, whereas the lactones activity is assumed as the physio/pathological one. This study is aimed to predict the location of the PON1 active site within PON1 crystal structure, and the lactone structure suitability as PON1 ligand, by employing modeling techniques. Based on such calculations the ligands-PON1 interactions were characterized, and relating lactones rate of hydrolysis revealed an inverse correlation with the docking energy of the ligands-PON1 complex, and a direct correlation with the lactone side chain length. In conclusion, this study characterized the PON1 possible active site and proposes a tool which may make it possible to envisage the structure of potential endogenous and exogenous lactones such as the PON1 ligand.
Tavori
Hagai
H
Laboratory of Natural Medicinal Compounds, MIGAL-Galilee Technology Center, PO Box 831, Kiryat Shmona 11016, Israel.
Khatib
Soliman
S
Aviram
Michael
M
Vaya
Jacob
J
D043303:Aryldialkylphosphatase / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D003198:Computer Simulation; D007783:Lactones / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D012984:Software; D013329:Structure-Activity Relationship
D007783:Lactones; D008024:Ligands; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human