Lipoxygenase

Lipoxygenases (EC 1.13.11.-) (LOX) are a family of (non-heme) iron-containing enzymes, more specifically oxidative 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.

Biochemistry

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 Protein domain § Domains and protein flexibility), 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.g. leukotrienes, hepoxilins, and various specialized pro-resolving mediators, or reduced by ubiquitous cellular glutathione peroxidases to a hydroxy group thereby forming hydroxylated (—OH) polyunsaturated fatty acids such as the hydroxyeicosatetraenoic acids and HODEs (i.e. hydroxyoctadecaenoic acids).

Polyunsaturated fatty acids that serve as substrates for one or more of the lipoxygenases include the omega 6 fatty acids, arachidonic acid, linoleic acid, dihomo-γ-linolenic acid, and adrenic acid; the omega-3 fatty acids, eicosapentaenoic acid, docosahexaenoic acid, and alpha-linolenic acid; and the omega-9 fatty acid, mead acid.