5-Hydroxyeicosatetraenoic acid
Names | |
---|---|
Preferred IUPAC name
(5S,6E,8Z,11Z,14Z)-5-Hydroxyicosa-6,8,11,14-tetraenoic acid | |
Other names
5-HETE, 5(S)-HETE
| |
Identifiers | |
3D model (
JSmol ) |
|
ChEBI | |
ChEMBL | |
ChemSpider | |
ECHA InfoCard
|
100.161.309 |
IUPHAR/BPS |
|
PubChem CID
|
|
UNII | |
| |
| |
Properties | |
C20H32O3 | |
Molar mass | 320.473 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
|
5-Hydroxyeicosatetraenoic acid (5-HETE, 5(S)-HETE, or 5S-HETE) is an
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. They are therefore a family of structurally related metabolites. Animal studies and a limited set of human studies suggest that this family of metabolites serve as
Among the 5(S)-HETE family members, 5(S)-HETE takes precedence over the other members of this family because it was the first to be discovered and has been studied far more thoroughly. However, 5-oxo-ETE is the most potent member of this family and therefore may be its critical member with respect to physiology and pathology. 5-OxoETE has gained attention in recent studies.
Nomenclature
5-Hydroxyeicosatetraenoic acid is more properly termed 5(S)-hydroxyicosatetraenoic acid or 5(S)-HETE) to signify the (S)
History of discovery
The Nobel laureate, Bengt I. Samuelsson, and colleagues first described 5(S)-HETE in 1976 as a metabolite of arachidonic acid made by rabbit neutrophils.[1] Biological activity was linked to it several years later when it was found to stimulate human neutrophil rises in cytosolic calcium, chemotaxis, and increases in their cell surface adhesiveness as indicated by their aggregation to each other.[2] Since a previously discovered arachidonic acid metabolite made by neutrophils, leukotriene B4 (LTB4), also stimulates human neutrophil calcium rises, chemotaxis, and auto-aggregation and is structurally similar to 5(S)-HETE in being a 5(S)-hydroxy-eicosateraenoate, it was assumed that 5(S)-HETE stimulated cells through the same cell surface receptors as those used by LTB4 viz., the leukotriene B4 receptors. However, further studies in neutrophils indicated that 5(S)-HETE acts through a receptor distinct from that used by LTB4 as well as various other neutrophil stimuli. This 5(S)-HETE receptor is termed the oxoeicosanoid receptor 1 (abbreviated as OXER1).[3][4]
5(S)-HETE production
5(S)-HETE is a product of the cellular metabolism of the n-6
Alternatively, 5(S)-HpETE may be further metabolized to its
The selective synthesis of 5(S)-HETE (i.e. synthesis of 5(S)-HETE without concurrent synthesis of 5(R)-HETE) by cells is dependent on, and generally proportionate to, the presence and levels of its forming enzyme, ALOX5. Human ALOX5 is highly expressed in cells that regulate
5(S)-HETE may also be made in combination with 5(R)-HETE along with numerous other (S,R)-hydroxy
5(S)-HETE metabolism
In addition to its intrinsic activity, 5(S)-ETE can serve as an intermediate that is converted to other bioactive products. Most importantly,
5-HEDH acts bi-directionally: it preferentially oxygenates 5(S)-HETE to 5-oxo-ETE in the presence of excess NADH+ but preferentially reduces 5-oxo-ETE back to 5(S)-HETE in the presence of excess NADPH. Since cells typically maintain far higher levels of NADPH than NADP+, they usually make little or no 5-oxo-ETE. When undergoing
Cells metabolize 5-(S)-HETE in other ways. They may use:[12][2][13][14][15]
- An acyltransferase to esterify 5(S)-HETE into their membrane phospholipids. This reaction may serve to storing 5(S)-HETE for its release during subsequent cell stimulation and/or alter the properties of cell membranes in functionally important ways.
- A cytochrome P450, probably CYP4F3, to metabolize 5(S)-HETE to 5(S),20-dihydroxy-eicosatetraenoate (5,20-diHETE). Since 5,20-diHETE is ~50- to 100-fold weaker than 5(S)-HETE in stimulating cells, this metabolism is proposed to represent a pathway for 5(S)-HETE inactivation.
- ALOX15 to metabolize 5(S)-HETE to 5(S),15(S)-dihydroxy-eicosatetraenoate (5,15-diHETE). 5,15-diHETE is ~3- to 10-fold weaker than 5(S)-HETE in stimulating cells.
- 12-Lipoxygenase (i.e. ALOX12) to metabolize 5(S)-HETE to 5(S),12(S)-diHETE. The activity of this product has not yet been fully evaluated.
- Cyclooxygenase-2 to metabolize 5(S)-HETE to 5(S),15(R)-diHETE and 5(S),11(R)-diHETE. The activity of these products have not yet been fully evaluated.
- Aspirin-treated cyclooxygenase-2 to metabolize 5(S)-HETE to 5(S),15(R)-diHETE. The activity of this product has not yet been fully evaluated.
Alternate pathways that make some of the above products include the: a) metabolism of 5(S)-HpETE to 5-oxo-ETE by
Mechanism of action
The OXER1 receptor
5(S)-HETE family members share a common receptor target for stimulating cells that differs from the receptors targeted by the other major products of ALOX5, i.e.,
Other receptors
Progress in proving the role of the 5-HETE family of agonists and their OXER1 receptor in human physiology and disease has been made difficult because mice, rats, and the other rodents so far tested lack OXER1. Rodents are the most common
PPARγ
5-Oxo-15(S)-hydroxy-ETE and to a lesser extent 5-oxo-ETE but not 5(S)-HETE also bind to and activate peroxisome proliferator-activated receptor gamma (PPARγ). Activation of OXER1 receptor and PPARγ by the oxo analogs can have opposing effects on cells. For example, 5-oxo-ETE-bound OXER1 stimulates while 5-oxo-ETE-bound PPARγ inhibits the proliferation of various types of human cancer cell lines.[21]
Other mechanisms
5(S)-HETE acylated into the phosphatidylethanolamines fraction of human neutrophil membranes is associated with the inhibition of these cells from forming neutrophil extracellular traps, i.e. extracellular DNA scaffolds which contain neutrophil-derived antimicrobial proteins that circulate in blood and have the ability to trap bacteria. It seems unlikely that this inhibition reflects involvement of OXER1.[22] 5-Oxo-ETE relaxes pre-contracted human bronchi by a mechanism that does not appear to involve OXER1 but is otherwise undefined.[17][23]
Clinical significance
Inflammation
5(S)-HETE and other family members were first detected as products of arachidonic acid made by stimulated human polymorphonuclear neutrophils (
These results given above suggest that members of the 5-oxo-ETE family and the OXER1 receptor or its orthologs may contribute to protection against microbes, the repair of damaged tissues, and pathological inflammatory responses in humans and other animal species.[12] However, an OXER1 ortholog is absent in mice and other rodents; while rodent tissues do exhibit responsiveness to 5-oxo-ETE, the lack of an oxer1 or other clear 5-oxoETE receptor in such valued animal models of diseases as rodents has impeded progress in our understanding of the physiological and pathological roles of 5-oxo-ETE.[19]
Allergy
The following human cell types or tissues that are implicated in allergic reactivity produce 5-HETE (stereoisomer typically not defined): alveolar macrophages isolated from asthmatic and non-asthmatic patients,
Among the 5-HETE family of metabolites, 5-oxo-ETE is implicated as the most likely member to contribute to allergic reactions. It has exceptionally high potency in stimulating the
The role of 5-HETE family agonists in the bronchoconstriction of airways (a hallmark of allergen-induced asthma) in humans is currently unclear. 5-HETE stimulates the contraction of isolated human bronchial muscle, enhances the ability of histamine to contract this muscle, and contracts guinea pig lung strips.[32] 5-Oxo-ETE also stimulates contractile responses in fresh bronchi, cultured bronchi, and cultured lung smooth muscle taken from guinea pigs but in direct contrast to these studies is reported to relax bronchi isolated from humans.[23][33][34] The latter bronchi contractile responses were blocked by cyclooxygenase-2 inhibition or a thromboxane A2 receptor antagonist and therefore appear mediated by 5-oxo-ETE-induced production of this thromboxane. In all events, the relaxing action of 5-oxo-ETE on human bronchi does not appear to involve OXER1.[17]
Cancer
The 5-oxo-ETE family of agonists have also been proposed to contribute to the growth of several types of human cancers. This is based on their ability to stimulate certain cultured human cancer cell lines to proliferate, the presence of OXER1 mRNA and/or protein in these cell lines, the production of 5-oxo-ETE family members by these cell lines, the induction of cell death (i.e. apoptosis) by inhibiting 5-lipoxygenase in these cells, and/or the overexpression of 5-lipoxygenase in tissue taken from the human tumors. Human cancers whose growth has been implicated by these studies as being mediated at least in part by a member(s) of the 5-oxo-ETE family include those of the prostate, breast, lung, ovary, and pancreas.[17][21][35][36]
Steroid production
5(S)-HETE and 5(S)-HpETE stimulate the production of
Rat and mouse cells lack OXER1. It has been suggested that the cited
Bone remodeling
In an in vitro mixed culture system, 5(S)-HETE is released by monocytes to stimulate, at sub-nanomolar concentrations, osteoclast-dependent bone reabsorption.[42] It also inhibits morphogenetic protein-2 (BMP-2)-induced bone-like nodule formation in mouse calvarial organ cultures.[43] These results allow that 5(S)-HETE and perhaps more potently, 5-oxo-ETE contribute to the regulation of bone remodeling.
Parturition
5(S)-HETE is: elevated in the human uterus during
Other actions
5(S)-HETE is reported to modulate tubuloglomerular feedback.[47] 5(S)-HpETE is also reported to inhibit the Na+/K+-ATPase activity of synaptosome membrane preparations prepared from rat cerebral cortex and may thereby inhibit synapse-dependent communications between neurons.[48]
5(S)-HETE acylated into phosphatidylethanolamine is reported to increase the stimulated production of
See also
- Arachidonic acid
- 5-Lipoxygenase
- 5-oxo-eicosatetraenoic acid
- Leukotriene B4
- Polyunsaturated fatty acid
- 12-Hydroxyeicosatetraenoic acid
- 15-Hydroxyeicosatetraenoic acid
References
- PMID 826538.
- ^ S2CID 3964822.
- ^ PMID 9829988.
- PMID 15893379.
- ^ PMID 25152163.
- S2CID 17299214.
- PMID 28125014.
- PMID 23752617.
- PMID 22002716.
- PMID 24056189.
- PMID 7258296.
- ^ PMID 25449650.
- PMID 16005201.
- PMID 22068350.
- PMID 25895638.
- PMID 8392058.
- ^ PMID 24056189.
- PMID 7803484.
- ^ PMID 26032638.
- ^ S2CID 8520991.
- ^ PMID 16154383.
- ^ PMID 21177434.
- ^ PMID 17499751.
- PMID 23934216.
- PMID 19450703.
- PMID 8143061.
- S2CID 35264541.
- PMID 6802816.
- PMID 6407484.
- PMID 7592874.
- PMID 17481554.
- PMID 6952280.
- PMID 17164130.
- S2CID 22972003.
- PMID 8609238.
- S2CID 22159108.
- S2CID 42436005.
- PMID 8359939.
- S2CID 36071655.
- PMID 10777507.
- S2CID 30710602.
- PMID 8486677.
- PMID 9645691.
- S2CID 27983033.
- PMID 2823315.
- PMID 2316568.
- ISBN 978-1416023289.
- PMID 9199200.
- PMID 3004591.