Interactions of glutathione transferases with 4-hydroxynonenal

被引:85
作者
Balogh, Larissa M. [1 ]
Atkins, William M. [2 ]
机构
[1] Pfizer Inc, Dept Pharmacokinet Dynam & Metab, Pfizer Global Res & Dev, Groton, CT 06340 USA
[2] Univ Washington, Dept Med Chem, Seattle, WA 98195 USA
基金
美国国家卫生研究院;
关键词
Oxidative stress; glutathione transferase A4-4; GSHNE; 4-hydroxynonenal-adducts; LIPID-PEROXIDATION PRODUCT; C-TERMINAL REGION; MILD COGNITIVE IMPAIRMENT; MASS-SPECTROMETRIC CHARACTERIZATION; HIGH CATALYTIC EFFICIENCY; HUMAN SERUM-ALBUMIN; S-TRANSFERASE; OXIDATIVE STRESS; ALZHEIMERS-DISEASE; CAENORHABDITIS-ELEGANS;
D O I
10.3109/03602532.2011.558092
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Electrophilic products of lipid peroxidation are important contributors to the progression of several pathological states. The prototypical alpha,beta-unsaturated aldehyde, 4-hydroxynonenal (HNE), triggers cellular events associated with oxidative stress, which can be curtailed by the glutathione-dependent elimination of HNE. The glutathione transferases (GSTs) are a major determinate of the intracellular concentration of HNE and can influence susceptibility to toxic effects, particularly when HNE and GST levels are altered in disease states. In this article, we provide a brief summary of the cellular effects of HNE, followed by a review of its GST-catalyzed detoxification, with an emphasis on the structural attributes that play an important role in the interactions with alpha-class GSTs. Some of the key determining characteristics that impart high alkenal activity reside in the unique C-terminal interactions of the GSTA4-4 enzyme. Studies encompassing both kinetic and structural analyses of related isoforms will be highlighted, with additional attention to stereochemical aspects that demonstrate the capacity of GSTA4-4 to detoxify both enantiomers of the biologically relevant racemic mixture while generating a select set of diastereomeric products with subsequent implications. A summary of the literature that examines the interplay between GSTs and HNE in model systems relevant to oxidative stress will also be discussed to demonstrate the magnitude of importance of GSTs in the overall detoxification scheme.
引用
收藏
页码:165 / 178
页数:14
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