Eicosanoid turnover

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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Eicosanoids are 20-carbon fatty acids, where the usual focus is the polyunsaturated analogue arachidonic acid and its metabolites. Arachidonic acid is thought primarily to derive from phospholipase A2 action on membrane phosphatidylcholine, and may be re-cycled to form phospholipid through conjugation with coenzyme A and subsequently glycerol derivatives. Oxidative metabolism of arachidonic acid is conducted through three major enzymatic routes: cyclooxygenases; lipoxygenases and cytochrome P450-like epoxygenases, particularly CYP2J2. Isoprostanes are structural analogues of the prostanoids (hence the nomenclature D-, E-, F-isoprostanes and isothromboxanes), which are produced in the presence of elevated free radicals in a non-enzymatic manner, leading to suggestions for their use as biomarkers of oxidative stress. Molecular targets for their action have yet to be defined.

Cyclooxygenase

Overview

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Prostaglandin (PG) G/H synthase, most commonly referred to as cyclooxygenase (COX, (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate,hydrogen-donor : oxygen oxidoreductase) activity, catalyses the formation of PGG2 from arachidonic acid. Hydroperoxidase activity inherent in the enzyme catalyses the formation of PGH2 from PGG2. COX-1 and -2 can be nonselectively inhibited by ibuprofen, ketoprofen, naproxen, indomethacin and paracetamol (acetaminophen). PGH2 may then be metabolised to prostaglandins and thromboxanes by various prostaglandin synthases in an apparently tissue-dependent manner.

Enzymes

COX-1 Show summary » More detailed page

COX-2 Show summary » More detailed page

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Prostaglandin synthases

Overview

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Subsequent to the formation of PGH2, the cytochrome P450 activities thromboxane synthase (CYP5A1, TBXAS1, P24557 , EC 5.3.99.5) and prostacyclin synthase (CYP8A1, PTGIS, Q16647, EC 5.3.99.4) generate thromboxane A2 and prostacyclin (PGI2), respectively. Additionally, multiple enzyme activities are able to generate prostaglandin E2 (PGE2), prostaglandin D2 (PGD2) and prostaglandin F (PGF). PGD2 can be metabolised to 9α,11β-prostacyclin F through the multifunctional enzyme activity of AKR1C3. PGE2 can be metabolised to 9α,11β-prostacyclin F through the 9-ketoreductase activity of CBR1. Conversion of the 15-hydroxyecosanoids, including prostaglandins, lipoxins and leukotrienes to their keto derivatives by the NAD-dependent enzyme HPGD leads to a reduction in their biological activity.

Enzymes

CYP5A1 Show summary »

Prostacyclin synthase (CYP8A1) Show summary »

mPGES1 Show summary »

mPGES2 Show summary »

cPGES Show summary »

L-PGDS Show summary »

H-PGDS Show summary »

AKR1C3 Show summary »

CBR1 Show summary »

HPGD Show summary »

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Lipoxygenases

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The lipoxygenases (LOXs) are a structurally related family of non-heme iron dioxygenases that function in the production, and in some cases metabolism, of fatty acid hydroperoxides. For arachidonic acid as substrate, these products are hydroperoxyeicosatetraenoic acids (HPETEs). In humans there are five lipoxygenases, the 5S-(arachidonate : oxygen 5-oxidoreductase), 12R-(arachidonate 12-lipoxygenase, 12R-type), 12S-(arachidonate : oxygen 12-oxidoreductase), and two distinct 15S-(arachidonate : oxygen 15-oxidoreductase) LOXs that oxygenate arachidonic acid in different positions along the carbon chain and form the corresponding 5S-, 12S-, 12R-, or 15S-hydroperoxides, respectively.

Enzymes

5-LOX Show summary » More detailed page

12R-LOX Show summary »

12S-LOX Show summary »

15-LOX-1 Show summary »

15-LOX-2 Show summary »

E-LOX Show summary »

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Leukotriene and lipoxin metabolism

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Leukotriene A4 (LTA4), produced by 5-LOX activity, and lipoxins may be subject to further oxidative metabolism; ω-hydroxylation is mediated by CYP4F2 and CYP4F3, while β-oxidation in mitochondria and peroxisomes proceeds in a manner dependent on coenzyme A conjugation. Conjugation of LTA4 at the 6 position with reduced glutathione to generate LTC4 occurs under the influence of leukotriene C4 synthase, with the subsequent formation of LTD4 and LTE4, all three of which are agonists at CysLT receptors. LTD4 formation is catalysed by γ-glutamyltransferase, and subsequently dipeptidase 2 removes the terminal glycine from LTD4 to generate LTE4. Leukotriene A4 hydrolase converts the 5,6-epoxide LTA4 to the 5-hydroxylated LTB4, an agonist for BLT receptors. LTA4 is also acted upon by 12S-LOX to produce the trihydroxyeicosatetraenoic acids lipoxins LXA4 and LXB4. Treatment with a LTA4 hydrolase inhibitor in a murine model of allergic airway inflammation increased LXA4 levels, in addition to reducing LTB4, in lung lavage fluid [39].

LTA4 hydrolase is also involved in biosynthesis of resolvin Es. aspirin has been reported to increase endogenous formation of 18S-hydroxyeicosapentaenoate (18S-HEPE) compared with 18R-HEPE, a resolvin precursor. Both enantiomers may be metabolised by human recombinant 5-LOX; recombinant LTA4 hydrolase converted chiral 5S(6)-epoxide-containing intermediates to resolvin E1 and 18S-resolvin E1 [35].

Enzymes

Leukotriene C4 synthase Show summary »

γ-Glutamyltransferase Show summary »

Dipeptidase 1 Show summary » More detailed page

Dipeptidase 2 Show summary »

Leukotriene A4 hydrolase Show summary » More detailed page

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References

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