Antioxidative function and substrate specificity of NAD(P)H-dependent alkenal/one oxidoreductase. A new role for leukotriene B4 12-hydroxydehydrogenase/15-oxoprostaglandin 13-reductase

Ryan A. Dick, Mi Kyoung Kwak, Thomas R. Sutter, Thomas W. Kensler

Research output: Contribution to journalArticlepeer-review

Abstract

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 x 103 min-1; kcat/Km = 3.3 x 107 min-1 M-1) and acrolein (kcat = 2.2 x 102 min-1; kcat/Km = 1.5 x 106 min-1 M-1) and common industrial compounds such as ethyl vinyl ketone (kcat = 9.6 x 103 min -1; kcat/Km = 8.8 x 107 min -1 M-1) and 15-oxoprostaglandin El (k cat = 2.4 x 103 min-1; kcat/K m = 2.4 x 109 min-1 M-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.

Original languageEnglish (US)
Pages (from-to)40803-40810
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number44
DOIs
StatePublished - Nov 2 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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