15-Hydroxyeicosatetraenoic acid (also termed 15-HETE, 15(S)-HETE, and 15S-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. Various cell types metabolize arachidonic acid to 15(S)-hydroperoxyeicosatetraenoic acid (15(S)-HpETE). This initial hydroperoxide product is extremely short-lived in cells: if not otherwise metabolized, it is rapidly reduced to 15(S)-HETE. Both of these metabolites, depending on the cell type which forms them, can be further metabolized to 15-oxo-eicosatetraenoic acid (15-oxo-ETE), 5(S),15(S)-dihydroxy-eicosatetraenoic acid (5(S),15(S)-diHETE), 5-oxo-15(S)-hydroxyeicosatetraenoic acid (5-oxo-15(S)-HETE), a subset of specialized pro-resolving mediators viz., the lipoxins, a class of pro-inflammatory mediators, the eoxins, and other products that have less well-defined activities and functions. Thus, 15(S)-HETE and 15(S)-HpETE, in addition to having intrinsic biological activities, are key precursors to numerous biologically active derivatives.
Some cell types (e.g. platelets) metabolize arachidonic acid to the stereoisomer of 15(S)-HpETE, 15(R)-HpETE. Both stereoisomers may also be formed as result of the metabolism of arachidonic acid by cellular microsomes or as a result of arachidonic acid auto-oxidation. Similar to 15(S)-HpETEs, 15(R)-HpETE may be rapidly reduced to 15(R)-HETE. These R,S stereoisomers differ only in having their hydroxy residue in opposite orientations. While the two R stereoisomers are sometimes referred to as 15-HpETE and 15-HETE, proper usage should identify them as R stereoisomers. 15(R)-HpETE and 15(R)-HETE lack some of the activity attributed to their S stereoisomers but can be further metabolized to bioactive products viz., the 15(R) class of lipoxins (also termed epi-lipoxins).
15(S)-HETE, 15(S)-HpETE, and many of their derivative metabolites are thought to have physiologically important functions. They appear to act as hormone-like autocrine and paracrine signaling agents that are involved in regulating inflammatory and perhaps other responses. Clinically, drugs that are stable analogs, and therefore mimic the anti-inflammatory actions of the lipoxins and drugs that block the production or actions of the pro-inflammatory eoxins may prove useful for treating acute and chronic inflammatory disorders.
Nomenclature and stereoisomers
15(S)-HETE is unambiguously designated by a shortened version of its IUPAC name viz., 15(S)-hydroxy-5Z,8Z,11Z,13E-eicosatetraenoic acid. In this terminology S refers to the absolute configuration of the chirality of the hydroxy functional group at carbon position 15. Its 15(R) enantiomer is designated 15(R)-hydroxy-5Z,8Z,11Z,13E-eicosatetraenoic acid. Z and E give the cis–trans isomerism about each double bond at carbon positions 5, 8, 11, and 13 with Z indicating cis and E indicating trans isomerism. Both stereoisomers are produced from their corresponding S and R 15-HpETE stereoisomers, i.e. 15(S)-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid (15(S)-HpETE) and 15(R)-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid (15(R)-HpETE).
Production
Human cells release arachidonic acid (i.e. 5Z,8Z,11Z,14Z-eicosatetraenoic acid) from its storage site in phospholipids by reactions that involve phospholipase C and/or lipase enzymes. This release is stimulated or enhanced by cell stimulation. The freed arachidonic acid is then converted to 15-hydroperoxy/hydroxy products by one or more of the following five pathways.
15-Lipoxygenase-1: Cells metabolize arachidonic acid with 15-lipoxygenase-1 (i.e., 15-LO-1, ALOX15) to form 15(S)-HpETE as a major product and 12(S)-hydroperoxy-5Z,8Z,10E,15Z-eicosatetraenoic acid (12(S)-HpETE) and 14(S),15(S)-trans-oxido-5Z,8Z,11Z-14,15-leukotriene A4 as minor products; 15(S)-HpETE and 12(S)-HpETE are rapidly converted to 15(S)-HETE and 12(S)-hydroxy-5Z,8Z,10E,15Z-eicosatetraenoic acid (12(S)-hydroxyeicosatetraenoic acid), (i.e. 12(S)-HETE), respectively, or further metabolized through other enzyme pathways; 14(S),15(S)-trans-oxido-5Z,8Z,11Z-14,15-leukotriene A4 is metabolized by 15-LO-1 to various isomers of 8,15(S)-dihydroxy-5S,8S,11Z,13S-eicosatetraenoic acids, e.g. 8,15(S)-LTB4's.
15-Lipoxygenase-2: Cells also used 15-lipoxygenase 2 (i.e. 15-LOX-2 or ALOX15B) to make 15(S)-HpETE and 15(S)-HETE. However this enzyme has a preference for metabolizing linoleic acid rather than arachidonic acid. It therefore forms linoleic acid metabolites (e.g. 13-hydoxyperoxy/hydroxy-octadecadienoic and 9-hydroperoxy/hydroxyl-octadecadienoic acids) in greater amounts than 15(S)-HpETE and 15(S)-HETE. 15-LOX-2 also differs from 15-LOX-1 in that it does not make 12(S)-HpETE or the leukotriene A4 isomer cited above.