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Concept
Lipoxygenase
Summary
Lipoxygenases () are a family of (non-heme) iron-containing enzymes most of which catalyze the dioxygenation of polyunsaturated fatty acids in lipids containing a cis,cis-1,4- pentadiene into cell signaling agents that serve diverse roles as autocrine signals that regulate the function of their parent cells, paracrine signals that regulate the function of nearby cells, and endocrine signals that regulate the function of distant cells.
The lipoxygenases are related to each other based upon their similar genetic structure and dioxygenation activity. However, one lipoxygenase, ALOXE3, while having a lipoxygenase genetic structure, possesses relatively little dioxygenation activity; rather its primary activity appears to be as an isomerase that catalyzes the conversion of hydroperoxy unsaturated fatty acids to their 1,5-epoxide, hydroxyl derivatives.
Lipoxygenases are found in eukaryotes (plants, fungi, animals, protists); while the third domain of terrestrial life, the archaea, possesses proteins with a slight (~20%) amino acid sequence similarity to lipoxygenases, these proteins lack iron-binding residues and therefore are not projected to possess lipoxygenase activity.
Based on detailed analyses of 15-lipoxygenase 1 and stabilized 5-lipoxygenase, lipoxygenase structures consist of a 15 kilodalton N-terminal beta barrel domain, a small (e.g. ~0.6 kilodalton) linker inter-domain (see ), and a relatively large C-terminal catalytic domain which contains the non-heme iron critical for the enzymes' catalytic activity. Most of the lipoxygenases (exception, ALOXE3) catalyze the reaction Polyunsaturated fatty acid + O2 → fatty acid hydroperoxide in four steps:
the rate-limiting step of hydrogen abstraction from a bisallylic methylene carbon to form a fatty acid radical at that carbon
rearrangement of the radical to another carbon center
addition of molecular oxygen (O2) to the rearranged carbon radical center thereby forming a peroxy radical(—OO·) bond to that carbon
reduction of the peroxy radical to its corresponding anion (—OO−)
The (—OO−) residue may then be protonated to form a hydroperoxide group (—OOH) and further metabolized by the lipoxygenase to e.
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5-Hydroxyeicosatetraenoic acid
5-Hydroxyeicosatetraenoic acid (5-HETE, 5(S)-HETE, or 5S-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. It is produced by diverse cell types in humans and other animal species. These cells may then metabolize the formed 5(S)-HETE to 5-oxo-eicosatetraenoic acid (5-oxo-ETE), 5(S),15(S)-dihydroxyeicosatetraenoic acid (5(S),15(S)-diHETE), or 5-oxo-15-hydroxyeicosatetraenoic acid (5-oxo-15(S)-HETE). 5(S)-HETE, 5-oxo-ETE, 5(S),15(S)-diHETE, and 5-oxo-15(S)-HETE, while differing in potencies, share a common mechanism for activating cells and a common set of activities.
Eicosanoid
Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosanoids are a sub-category of oxylipins, i.e. oxidized fatty acids of diverse carbon units in length, and are distinguished from other oxylipins by their overwhelming importance as cell signaling molecules.
Specialized pro-resolving mediators
Specialized pro-resolving mediators (SPM, also termed specialized proresolving mediators) are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of lipoxygenase, cyclooxygenase, and cytochrome P450 monooxygenase enzymes. Pre-clinical studies, primarily in animal models and human tissues, implicate SPM in orchestrating the resolution of inflammation. Prominent members include the resolvins and protectins.