Inactivation of glutathione reductase by 4-hydroxynonenal and other endogenous aldehydes

• Published in: Biochemical pharmacology Vol. 53; no. 8; pp. 1133 - 1140
• Main Authors: Vander Jagt, David L., Hunsaker, Lucy A., Vander Jagt, Timothy J., Gomez, Manuel S., Gonzales, Donna M., Deck, Lorraine M., Royer, Robert E.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 25-04-1997; Elsevier Science
• Subjects: 3-deoxyglucosone; 4-hydroxynonenal; acrolein; Acrolein - analogs & derivatives; Acrolein - pharmacology; Aldehydes - metabolism; Aldehydes - pharmacology; Amino Acids - analysis; Biological and medical sciences; Deoxyglucose - analogs & derivatives; Deoxyglucose - pharmacology; Enzyme Activation; General and cellular metabolism. Vitamins; glutathione reductase; Glutathione Reductase - antagonists & inhibitors; Glutathione Reductase - chemistry; Glutathione Reductase - metabolism; Ketoses - pharmacology; Medical sciences; methylglyoxal; Pharmacology. Drug treatments; Pyruvaldehyde - pharmacology; Spectrometry, Fluorescence; xylosone; methylglyoxal; 3-deoxyglucosone; glutathione reductase; xylosone; 4-hydroxynonenal; acrolein; Enzyme; Glutathione reductase (NADPH); Glyoxal derivatives; Enzyme inhibitor; Glucose; Aldehyde; Antioxidant; Inactivation; Biological activity; Xylose; Acrolein; Oxidoreductases; Kinetics; Mechanism of action
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(97)00090-7

4-Hydroxynonenal, a product of oxidative degradation of unsaturated lipids, is an endogenous reactive α,β-unsaturated aldehyde with numerous biological activities. 4-Hydroxynonenal rapidly inactivated glutathione reductase in an NADPH-dependent reaction. Inactivation appears to involve the initial formation of an enzyme-inactivator complex,
K
D
= 0.5
μM, followed by the inactivation reaction,
k = 1.3 × 10
−2min.
−1. α,β-Unsaturated aldehydes such as acrolein, crotonaldehyde, and cinnamaldehyde also inactivated glutathione reductase, although rates varied widely. Inactivation of glutathione reductase by α,β-unsaturated aldehydes was followed by slower NADPH-independent reactions that led to formation of nonfluorescent cross-linked products, accompanied by loss of lysine and histidine residues. Other reactive endogenous aldehydes such as methylglyoxal, 3-deoxyglucosone, and xylosone inactivated glutathione reductase by an NADPH-independent mechanism, with methylglyoxal being the most reactive. However, 2-oxoaldehydes were much less effective than 4-hydroxynonenal. Inactivation of glutathione reductase by these 2-oxoaldehydes was followed by slower reactions that led to the formation of fluorescent cross-linked products over a period of several weeks. These changes were accompanied by loss of arginine residues. Thus, the sequence of events is different for inactivation and modification of glutathione reductase by α,β-unsaturated aldehydes compared with 2-oxoaldehydes with respect to kinetics, NADPH requirements, fluorescence changes, and loss of amino acid residues. The ability of 4-hydroxynonenal at low concentrations to inactivate glutathione reductase, a central antioxidant enzyme, suggests that oxidative degradation of unsaturated lipids may initiate a positive feedback loop that enhances the potential for oxidative damage.