Structural basis for catalytic activity and enzyme polymerization of phospholipid hydroperoxide glutathione peroxidase-4 (GPx4).

Phospholipid hydroperoxide glutathione peroxidase (GPx4) is a moonlighting selenoprotein, which has been implicated in anti-oxidative defense, sperm development, and cerebral embryogenesis. Among GPx-isoforms, GPx4 is unique because of its capability to reduce complex lipid hydroperoxides and its tendency toward polymerization, but the structural basis for these properties remained unclear. To address this, we solved the crystal structure of the catalytically active U46C mutant of human GPx4 to 1.

Expression of 12/15-lipoxygenase attenuates intracellular lipid deposition during in vitro foam cell formation.

Objective: Lipoxygenases with different positional specificity have been implicated in atherogenesis, but the precise roles of the various isoforms remain unclear. Because of its capability of oxidizing low-density lipoprotein (LDL) to an atherogenic form, 12/15-lipoxygenases have been suggested to initiate LDL oxidation in vivo; thus, these enzymes may exhibit pro-atherogenic activities. However, in several rabbit atherosclerosis models, the enzyme appears to act atheroprotective.

Amino acid differences in the deduced 5-lipoxygenase sequence of CAST atherosclerosis-resistance mice confer impaired activity when introduced into the human ortholog.

Objective: The mouse strain CON6, which was generated by breeding athero-resistant CAST mice into an athero-susceptible B6 background, exhibits almost complete resistance to atherosclerosis. An athero-resistance gene cluster has been localized at the central region of chromosome 6, and among the candidate genes of this locus, the 5-lipoxygenase has attracted particular attention because of its involvement in the biosynthesis of proinflammatory leukotrienes. Comparison of 5-lipoxygenase genomic sequences of B6 and CON6 mice indicated 2 conserved amino acid exchanges in the CON6 animals, but the functional impact of these mutations has not been defined.