期刊
CHEMICAL RESEARCH IN TOXICOLOGY
卷 20, 期 9, 页码 1260-1268出版社
AMER CHEMICAL SOC
DOI: 10.1021/tx7000948
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资金
- NCCIH NIH HHS [P50 AT 00477] Funding Source: Medline
- NCI NIH HHS [P30 CA 13148] Funding Source: Medline
- NCRR NIH HHS [S10 RR 17261] Funding Source: Medline
Creatine kinase reversibly catalyzes the transfer of the high-energy phosphoryl group from phosphocreatine to MgADP for rapid regeneration of ATP. It is hypothesized that factors which perturb creatine kinase activity, such as reactive oxygen species resulting from oxidative stress, could have a major role in the pathogenesis of diseases, particularly in the brain, where the level of ATP utilization is high. The reactive aldehyde 4-hydroxy-2-nonenal is a major secondary product of lipid peroxidation caused by oxidative stress; the levels of both free and protein-bound 4-hydroxy-2-nonenal are increased in Alzheimer's disease brain. Preliminary reports indicated that creatine kinase had lower activity in Alzheimer's disease brain. In this study, we investigated the structural and functional consequences of reacting the cytosolic brain isoform of creatine kinase with 4-hydroxy-2-nonenal at pathophysiologically relevant concentrations of 4-hydroxy-2-nonenal (10-300,mu M). Dose-dependent reduction of enzyme activity was observed and, for the first time, correlated with 4-hydroxy-2-nonenal adduct formation on specific amino acid residues, including the active site residues His66, His191, Cys283, and His296 as determined by Fourier transformion cyclotron resonance mass spectrometry.
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