title: Demonstration of HNE-related aldehyde formation via lipoxygenase-catalyzed synthesis of a bis-allylic dihydroperoxide intermediate.
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.
authors.affiliation: Department of Pharmacology and the Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Zheng
authors.forename: Alan R
authors.initials: AR
authors.lastname: Brash
mesh_terms: D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D037421:Anthozoa / Q000201:enzymology; D055162:Biocatalysis; D006861:Hydrogen Peroxide / Q000737:chemistry* / Q000378:metabolism*; D008054:Lipid Peroxides / Q000737:chemistry / Q000378:metabolism; D008084:Lipoxygenase / Q000378:metabolism*; D015394:Molecular Structure
chemical_list: D000447:Aldehydes; D008054:Lipid Peroxides; D006861:Hydrogen Peroxide; D008084:Lipoxygenase; C027576:4-hydroxy-2-nonenal