Human carotid lesion linoleic acid hydroperoxide inhibits paraoxonase 1 (PON1) activity via reaction with PON1 free sulfhydryl cysteine 284

Hagai Tavori, Michael Aviram, Soliman Khatib, Ramadan Musa, Dalit Mannheim, Ron Karmeli, Jacob Vaya

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Paraoxonase 1 (PON1) is an HDL-associated lactonase with antiatherogenic properties. These include dampening the oxidation properties of human carotid lesion lipid extract (LLE), which in turn inactivates the enzyme. The aims of this study were to identify the PON1 inhibitor in LLE and explore the mechanism of inhibition. LLE inhibited both recombinant PON1 and HDL-PON1 lactonase activity in a dose- and time-dependent manner. Addition of antioxidants or electrophiles to LLE did not prevent PON1 inhibition. LLE was unable to inhibit a PON1 mutant lacking Cys284, whereas it did inhibit all other PON1 mutants tested. The inhibitor in the LLE was identified as linoleic acid hydroperoxide (LA-OOH) and inhibition was specific to this hydroperoxide. During its inhibition, PON1 acted like a peroxidase enzyme, reducing LA-OOH to LA-hydroxide via its Cys284. A similar reaction occurred with external thiols, such as DDT or cysteine, which also prevented PON1 inhibition and restored enzyme activity after inhibition. Thus, the antiatherogenic properties of HDL could be, at least in part, related to the sulfhydryl-reducing characteristics of its associated PON1, which are further protected and recycled by the sulfhydryl amino acid cysteine.

Original languageEnglish (US)
Pages (from-to)148-156
Number of pages9
JournalFree Radical Biology and Medicine
Volume50
Issue number1
DOIs
StatePublished - Jan 1 2011
Externally publishedYes

Keywords

  • Atherosclerosis
  • Carotid lesion
  • Free radicals
  • Free thiols
  • Linoleic acid hydroperoxide
  • Oxidative stress
  • Paraoxonase 1

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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