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 journalArticle

30 Citations (Scopus)

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

Fingerprint

Aryldialkylphosphatase
Cysteine
Lipids
Enzyme inhibition
Enzymes
linoleic acid hydroperoxide
DDT
Enzyme activity
Sulfhydryl Compounds
Hydrogen Peroxide
Peroxidase
Antioxidants

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Human carotid lesion linoleic acid hydroperoxide inhibits paraoxonase 1 (PON1) activity via reaction with PON1 free sulfhydryl cysteine 284. / Tavori, Hagai; Aviram, Michael; Khatib, Soliman; Musa, Ramadan; Mannheim, Dalit; Karmeli, Ron; Vaya, Jacob.

In: Free Radical Biology and Medicine, Vol. 50, No. 1, 01.01.2011, p. 148-156.

Research output: Contribution to journalArticle

Tavori, Hagai ; Aviram, Michael ; Khatib, Soliman ; Musa, Ramadan ; Mannheim, Dalit ; Karmeli, Ron ; Vaya, Jacob. / Human carotid lesion linoleic acid hydroperoxide inhibits paraoxonase 1 (PON1) activity via reaction with PON1 free sulfhydryl cysteine 284. In: Free Radical Biology and Medicine. 2011 ; Vol. 50, No. 1. pp. 148-156.
@article{0990042e28a74a6e8b66d9c28eea8a60,
title = "Human carotid lesion linoleic acid hydroperoxide inhibits paraoxonase 1 (PON1) activity via reaction with PON1 free sulfhydryl cysteine 284",
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.",
keywords = "Atherosclerosis, Carotid lesion, Free radicals, Free thiols, Linoleic acid hydroperoxide, Oxidative stress, Paraoxonase 1",
author = "Hagai Tavori and Michael Aviram and Soliman Khatib and Ramadan Musa and Dalit Mannheim and Ron Karmeli and Jacob Vaya",
year = "2011",
month = "1",
day = "1",
doi = "10.1016/j.freeradbiomed.2010.10.708",
language = "English (US)",
volume = "50",
pages = "148--156",
journal = "Free Radical Biology and Medicine",
issn = "0891-5849",
publisher = "Elsevier Inc.",
number = "1",

}

TY - JOUR

T1 - Human carotid lesion linoleic acid hydroperoxide inhibits paraoxonase 1 (PON1) activity via reaction with PON1 free sulfhydryl cysteine 284

AU - Tavori, Hagai

AU - Aviram, Michael

AU - Khatib, Soliman

AU - Musa, Ramadan

AU - Mannheim, Dalit

AU - Karmeli, Ron

AU - Vaya, Jacob

PY - 2011/1/1

Y1 - 2011/1/1

N2 - 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.

AB - 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.

KW - Atherosclerosis

KW - Carotid lesion

KW - Free radicals

KW - Free thiols

KW - Linoleic acid hydroperoxide

KW - Oxidative stress

KW - Paraoxonase 1

UR - http://www.scopus.com/inward/record.url?scp=78650687313&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78650687313&partnerID=8YFLogxK

U2 - 10.1016/j.freeradbiomed.2010.10.708

DO - 10.1016/j.freeradbiomed.2010.10.708

M3 - Article

C2 - 21044882

AN - SCOPUS:78650687313

VL - 50

SP - 148

EP - 156

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 0891-5849

IS - 1

ER -