Demonstration of HNE-related aldehyde formation via lipoxygenase-catalyzed synthesis of a bis-allylic dihydroperoxide intermediate

Chem Res Toxicol. 2013 Jun 17;26(6):896-903. doi: 10.1021/tx4000396. Epub 2013 May 23.

Abstract

One of the proposed pathways to the synthesis of 4-hydroxy-nonenal (HNE) and related aldehydes entails formation of an intermediate bis-allylic fatty acid dihydroperoxide. As a first direct demonstration of such a pathway and proof of principle, herein we show that 8R-lipoxygenase (8R-LOX) catalyzes the enzymatic production of the HNE-like product (11-oxo-8-hydroperoxy-undeca-5,9-dienoic acid) via synthesis of 8,11-dihydroperoxy-eicosa-5,9,12,14-tetraenoic acid intermediate. Incubation of arachidonic acid with 8R-LOX formed initially 8R-hydroperoxy-eicosatetraenoic acid (8R-HPETE), which was further converted to a mixture of products including a prominent HPNE-like enone. A new bis-allylic dihydroperoxide was trapped when the incubation was repeated on ice. Reincubation of this intermediate with 8R-LOX successfully demonstrated its conversion to the enone products, and this reaction was greatly accelerated by coincubation with NDGA, a reductant of the LOX iron. These findings identify a plausible mechanism that could contribute to the production of 4-hydroxy-alkenals in vivo.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aldehydes / chemistry
  • Aldehydes / metabolism*
  • Animals
  • Anthozoa / enzymology
  • Biocatalysis
  • Hydrogen Peroxide / chemistry*
  • Hydrogen Peroxide / metabolism*
  • Lipid Peroxides / chemistry
  • Lipid Peroxides / metabolism
  • Lipoxygenase / metabolism*
  • Molecular Structure

Substances

  • Aldehydes
  • Lipid Peroxides
  • Hydrogen Peroxide
  • Lipoxygenase
  • 4-hydroxy-2-nonenal