Identification of alpha-dicarbonyl scavengers for cellular protection against carbonyl stress |
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Authors: | Wondrak Georg T Cervantes-Laurean Daniel Roberts Michael J Qasem Jaber G Kim Moonsun Jacobson Elaine L Jacobson Myron K |
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Affiliation: | Department of Pharmacology and Toxicology, College of Pharmacy, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA. |
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Abstract: | Tissue deterioration and aging have long been associated with the accumulation of chemically induced protein and DNA damage. Reactive oxygen species (ROS) and reactive carbonyl species (RCS), especially alpha-dicarbonyl compounds, are key mediators of damage caused by oxidative stress, glycation, and UV-irradiation. The toxic effects of ROS are counteracted in vivo by antioxidants and antioxidant enzymes, and the deleterious effects of one RCS, methylglyoxal, are counteracted by a ubiquitous glyoxalase system. Carbonyl stress as a result of toxic effects of various mono-dicarbonyls (e.g. 4-hydroxynonenal) and alpha-dicarbonyls (e.g. glyoxal and deoxyosones) cannot be directly antagonized by antioxidants, and only a small number of biological carbonyl scavengers like glutathione (GSH) have been identified to date. We have developed a new screening method for the identification of carbonyl scavengers using a rapid glycation system that proceeds independent of oxygen and therefore, excludes identification of inhibitory compounds acting as antioxidants. Using this screening assay adapted to 96-well microtiter plates, we have identified the cysteine derivative 3,3-dimethyl-D-cysteine as a potent inhibitor of non-oxidative advanced glycation. Comparative kinetic analyses demonstrated the superior alpha-oxoaldehyde-scavenging activity of D-penicillamine over that of aminoguanidine. D-Penicillamine traps alpha-oxoaldehydes by forming a 2-acylthiazolidine derivative as shown by structure elucidation of reaction products between D-penicillamine and methylglyoxal or phenylglyoxal. We demonstrated that upon co-incubation, D-penicillamine protects human skin keratinocytes and fibroblasts (CF3 cells) against glyoxal- and methylglyoxal-induced carbonyl toxicity. Our research qualifies alpha-amino-beta-mercapto-beta,beta-dimethyl-ethane as a promising pharmacophore for the development of related alpha-dicarbonyl scavengers as therapeutic agents to protect cells against carbonyl stress. |
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Keywords: | ADP-ribose, adenosine 5′-diphosphoribose AGE, advanced glycation end product AGE-BSA, BSA modified with advanced glycation end products CML, Nε-carboxymethyllysine DTPA, diethylenetriamine-pentaacetic acid GOLD, glyoxal-lysine dimer MALDI-TOF-MS, matrix-assisted laser desorption ionization-time of flight-mass spectrometry MOLD, methylglyoxal-lysine dimer NAC, Nα-acetyl- smallcaps" >l-cysteine RCS, reactive carbonyl species ROS, reactive oxygen species. |
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