Characterization of the PON1 active site using modeling simulation, in relation to PON1 lactonase activity

Hagai Tavori, Soliman Khatib, Michael Aviram, Jacob Vaya

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7504-7509
Number of pages6
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number15
DOIs
StatePublished - Aug 1 2008
Externally publishedYes

Fingerprint

Lactones
Catalytic Domain
Computer simulation
Ligands
Organophosphates
Enzymes
Chain length
Hydrolysis
Crystal structure
Substrates

Keywords

  • Docking
  • Lactones
  • Lactonization
  • Modeling
  • Paraoxonase1

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Characterization of the PON1 active site using modeling simulation, in relation to PON1 lactonase activity. / Tavori, Hagai; Khatib, Soliman; Aviram, Michael; Vaya, Jacob.

In: Bioorganic and Medicinal Chemistry, Vol. 16, No. 15, 01.08.2008, p. 7504-7509.

Research output: Contribution to journalArticle

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AU - Vaya, Jacob

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N2 - 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.

AB - 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.

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