Small amounts of isotope-reinforced polyunsaturated fatty acids suppress lipid autoxidation.
Polyunsaturated fatty acids (PUFAs) undergo autoxidation and generate reactive carbonyl compounds that are toxic to cells and associated with apoptotic cell death, age-related neurodegenerative diseases, and atherosclerosis. PUFA autoxidation is initiated by the abstraction of bis-allylic hydrogen atoms. Replacement of the bis-allylic hydrogen atoms with deuterium atoms (termed site-specific isotope-reinforcement) arrests PUFA autoxidation due to the isotope effect. Kinetic competition experiments show that the kinetic isotope effect for the propagation rate constant of Lin autoxidation compared to that of 11,11-D(2)-Lin is 12.8 ± 0.6. We investigate the effects of different isotope-reinforced PUFAs and natural PUFAs on the viability of coenzyme Q-deficient Saccharomyces cerevisiae coq mutants and wild-type yeast subjected to copper stress. Cells treated with a C11-BODIPY fluorescent probe to monitor lipid oxidation products show that lipid peroxidation precedes the loss of viability due to H-PUFA toxicity. We show that replacement of just one bis-allylic hydrogen atom with deuterium is sufficient to arrest lipid autoxidation. In contrast, PUFAs reinforced with two deuterium atoms at mono-allylic sites remain susceptible to autoxidation. Surprisingly, yeast treated with a mixture of approximately 20%:80% isotope-reinforced D-PUFA:natural H-PUFA are protected from lipid autoxidation-mediated cell killing. The findings reported here show that inclusion of only a small fraction of PUFAs deuterated at the bis-allylic sites is sufficient to profoundly inhibit the chain reaction of nondeuterated PUFAs in yeast.
Department of Chemistry and Biochemistry and the Molecular Biology Institute, UCLA, 607 Charles E. Young Dr. E., Los Angeles, CA 90095-1569, USA.
Shauna
S
Hill
Connor R
CR
Lamberson
Libin
L
Xu
Randy
R
To
Hui S
HS
Tsui
Vadim V
VV
Shmanai
Andrei V
AV
Bekish
Agape M
AM
Awad
Beth N
BN
Marbois
Charles R
CR
Cantor
Ned A
NA
Porter
Catherine F
CF
Clarke
Mikhail S
MS
Shchepinov
D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism / Q000494:pharmacology; D003300:Copper / Q000494:pharmacology; D003903:Deuterium / Q000737:chemistry / Q000378:metabolism; D015118:Eicosapentaenoic Acid / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D019787:Linoleic Acid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015227:Lipid Peroxidation; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D014451:Ubiquinone / Q000378:metabolism
D000975:Antioxidants; D016877:Oxidants; D014451:Ubiquinone; D016718:Arachidonic Acid; D003300:Copper; D019787:Linoleic Acid; D015118:Eicosapentaenoic Acid; D003903:Deuterium