Thirty years with three-dimensional structures of lipoxygenases

被引:4
作者
Oliw, Ernst H. [1 ]
机构
[1] Uppsala Univ, Dept Pharmaceut Biosci, Box 591, S-75124 Uppsala, Sweden
关键词
Active site residues; Enzyme-substrate complexes; Oxidation mechanism; Substrate cavity; X-ray crystallography; BIS-ALLYLIC HYDROPEROXIDE; CRYSTAL-STRUCTURE; MANGANESE LIPOXYGENASE; ACTIVE-SITE; SOYBEAN LIPOXYGENASE-1; JASMONIC ACID; CYANOTHECE SP; FATTY-ACIDS; OLEIC-ACID; SUBSTRATE;
D O I
10.1016/j.abb.2023.109874
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The X-ray crystal structures of soybean lipoxygenase (LOX) and rabbit 15-LOX were reported in the 1990s. Subsequent 3D structures demonstrated a conserved U-like shape of the substrate cavities as reviewed here. The 8-LOX:arachidonic acid (AA) complex showed AA bound to the substrate cavity carboxylate-out with C10 at 3.4 angstrom from the iron metal center. A recent cryo-electron microscopy (EM) analysis of the 12-LOX:AA complex illustrated AA in the same position as in the 8-LOX:AA complex. The 15-and 12-LOX complexes with isoenzyme-specific inhibitors/substrate mimics confirmed the U-fold. 5-LOX oxidizes AA to leukotriene A4, the first step in biosynthesis of mediators of asthma. The X-ray structure showed that the entrance to the substrate cavity was closed to AA by Phe and Tyr residues of a partly unfolded alpha 2-helix. Recent X-ray analysis revealed that soaking with inhibitors shifted the short alpha 2-helix to a long and continuous, which opened the substrate cavity. The alpha 2-helix also adopted two conformations in 15-LOX. 12-LOX dimers consisted of one closed and one open subunit with an elongated alpha 2-helix. 13C-ENDOR-MD computations of the 9-MnLOX:linoleate complex showed carboxylate-out position with C11 placed 3.4 +/- 0.1 angstrom from the catalytic water. 3D structures have provided a solid ground for future research.
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页数:18
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