Journal of Biological Chemistry
Volume 276, Issue 44, 2 November 2001, Pages 40803-40810
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ENZYME CATALYSIS AND REGULATION
Antioxidative Function and Substrate Specificity of NAD(P)H- dependent Alkenal/one Oxidoreductase: A NEW ROLE FOR LEUKOTRIENE B412-HYDROXYDEHYDROGENASE/15-OXOPROSTAGLANDIN 13-REDUCTASE*

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There are several known routes for the metabolic detoxication of α,β-unsaturated aldehydes and ketones, including conjugation to glutathione and reduction and oxidation of the aldehyde to an alcohol and a carboxylic acid, respectively. In this study, we describe a fourth class of detoxication that involves the reduction of the α,β-carbon=carbon double bond to a single bond. This reaction is catalyzed by NAD(P)H-dependent alkenal/one oxidoreductase (AO), an enzyme heretofore known as leukotriene B4 12-hydroxydehydrogenase, 15-oxoprostaglandin 13-reductase, and dithiolethione-inducible gene-1. AO is shown to effectively reduce cytotoxic lipid peroxidation products such as 4-hydroxy-2-nonenal (HNE) (kcat = 4.0 × 103 min−1;kcat/Km = 3.3 × 107 min−1m−1) and acrolein (kcat = 2.2 × 102min−1; kcat/Km= 1.5 × 106 min−1m−1) and common industrial compounds such as ethyl vinyl ketone (kcat = 9.6 × 103 min−1;kcat/Km = 8.8 × 107 min−1m−1) and 15-oxoprostaglandin E1 (kcat = 2.4 × 103 min−1;kcat/Km = 2.4 × 109 min−1m−1). Furthermore, transfection of human embryonic kidney cells with a rat liver AO expression vector protected these cells from challenge with HNE. The concentration of HNE at which 50% of the cells were killed after 24 h increased from ∼15 µm in control cells to ∼70 µm in AO-transfected cells. Overexpression of AO also completely abolished protein alkylation by HNE at all concentrations tested (up to 30 µm). Thus, we describe a novel antioxidative activity of a previously characterized bioactive lipid-metabolizing enzyme that could prove to be therapeutically or prophylactically useful due to its high catalytic rate and inducibility.

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Published, JBC Papers in Press, August 27, 2001, DOI 10.1074/jbc.M105487200

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This work was supported in part by National Institutes of Health Grant CA39416.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Supported by National Institutes of Health Training Grant T32CA09243.