Eicosanoid biosynthesis

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Eicosanoids are signaling molecules, synthesized by most living creatures. (The IUPAC and the IUBMB use the equivalent term Icosanoid.^[1]) These oxygenated essential fatty acids are not stored within cells, but are generated as required. They derive from fatty acids, which are cleaved from larger molecules—phospholipids and diacylglycerols—found in the cell membrane and nuclear membrane.

The four classical eicosanoid families are generated by via two types of enzymes, each of which adds oxygen. Lipoxygenase yields leukotrienes. Cyclooxygenase yields the three prostanoids—prostaglandins, prostacyclin and thromboxanes. Several other oxidation paths yield additional bioactive signaling molecules—the non-classical eicosanoids.

Contents 1 Biosynthetic pathways 2 Peroxidation and reactive oxygen species 3 Biosynthesis of prostanoids 4 Biosynthesis of leukotrienes 5 References

[edit] Biosynthetic pathways

Overview article: Eicosanoid

Eicosanoid pathways

'Classical' eicosanoids	Other signaling molecules derived from 20-carbon essential fatty acids
The free fatty acid has two possible eicosanoid fates: 5-lipoxygenase pathway: Leukotrienes Cyclooxygenase pathway ("prostanoids"): Prostaglandins Prostacyclin Thromboxanes	Other oxygenation pathways make related products: 12-lipoxygenase pathway: Hepoxilins Lipoxins Epi-lipoxins Cytochrome P450 pathways: EETs Free radical peroxidation: Isoprostanes Isofurans	There is also ethanolamide or glycerol addition: Anandamide and other endocannabinoids

The first step of eicosanoid biosynthesis occurs when cell is activated by mechanical trauma, cytokines, growth factors or other stimuli. (The stimulus may even be an eicosanoid from a neighboring cell; the pathways are complex.) This triggers the release of a phospholipase at the cell wall. The phospholipase travels to the nuclear membrane. There, the phospholipase catalyzes ester hydrolysis of phospholipid (by A₂) or diacylglycerol (by phospholipase C). This frees a 20-carbon essential fatty acid. This hydrolysis appears to be the rate-determining step for eicosanoid formation.

The fatty acids may be released by any of several phospholipases. Of these, type IV cytosolic phospholipase A₂ (cPLA₂) is the key actor, as cells lacking cPLA₂ are generally devoid of eicosanoid synthesis. The phospholipase cPLA₂ is specific for phospholipids that contain AA, EPA or GPLA at the SN2 position. Interestingly, cPLA₂ may also release the lysophospholipid that becomes platelet-activating factor.^[2]

[edit] Peroxidation and reactive oxygen species

Next, the free fatty acid is oxygenated along any of several pathways; see the Pathways table. The eicosanoid pathways (via lipoxygenase or COX) add molecular oxygen (O₂). Although the fatty acid is symmetric, the resulting eicosanoids are chiral; the oxidation proceeds with high stereospecificity.

The oxidation of lipids is hazardous to cells, particularly when close to the nucleus. There are elaborate mechanisms to prevent unwanted oxidation. COX, the lipoxygenases and the phospholipases are tightly controlled—there are at least eight proteins activated to coordinate generation of leukotrienes. Several of these exist in multiple isoforms.^[3]

Oxidation by either COX or lipoxygenase releases reactive oxygen species (ROS) and the initial products in eicosanoid generation are themselves highly reactive peroxides. LTA₄ can form adducts with tissue DNA. Other reactions of lipoxygenases generate cellular damage; murine models implicate 15-lipoxygenase in the pathogenesis of atherosclerosis.^[4][5] The oxidation in eicosanoid generation is compartmentalized; this limits the peroxides' damage. The enzymes which are biosynthetic for eicosanoids (e.g. glutathione-S-transferases, epoxide hydrolases and carrier proteins) belong to families whose functions are largely involved with cellular detoxification. This suggests that eicosanoid signaling may have evolved from the detoxification of ROS.

The cell must realize some benefit from generating lipid hydroperoxides close-by its nucleus. PGs and LTs may signal or regulate DNA-transcription there; LTB₄ is ligand for PPARα.^[6] (See diagram at PPAR).

Structures of Selected Eicosanoids

Prostaglandin E1. The 5-member ring is characteristic of the class.	Thromboxane A2. Oxygens have moved into the ring.		Leukotriene B4. Note the 3 conjugated double bonds.
Prostacyclin I2. The second ring distinguishes it from the prostaglandins.		Leukotriene E4, an example of a cysteinyl leukotriene.

[edit] Biosynthesis of prostanoids

See Prostanoid#Biosynthesis.

Cyclooxygenase (COX) catalyzes the conversion of the free essential fatty acids to prostanoids by a two-step process. First, two molecules of O₂ are added as two peroxide linkages, and a 5-member carbon ring is forged near the middle of the fatty acid chain. This forms the short-lived, unstable intermediate Prostaglandin G (PGG). Next, one of the peroxide linkages sheds a single oxygen, forming PGH. (See diagrams and more detail of these steps at Cyclooxygenase).

All three classes of prostanoids originate from PGH. All have distinctive rings in the center of the molecule. They differ in their structures. The PGH compounds (parents to all the rest) have a 5-carbon ring, bridged by two oxygens (a peroxide.) As the example in Structures of Selected Eicosanoids figure shows, the derived prostaglandins contain a single, unsaturated 5-carbon ring. In prostacyclins, this ring is conjoined to another oxygen-containing ring. In thromboxanes the ring becomes a 6-member ring with one oxygen. The leukotrienes do not have rings. (See more detail, including the enzymes involved, in diagrams at Prostanoid.)

Several drugs lower inflammation by blocking prostanoid synthesis; see detail at Cyclooxygenase, Aspirin and NSAID.

[edit] Biosynthesis of leukotrienes

See Leukotriene#Biosynthesis.

The enzyme 5-lipoxygenase (5-LO) uses 5-lipoxygenase activating protein (FLAP) to convert arachidonic acid into 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which spontaneously reduces to 5-hydroxyeicosatetraenoic acid (5-HETE). The enzyme 5-LO acts again on 5-HETE to convert it into leukotriene A₄ (LTA₄), which may be converted into LTB₄ by the enzyme leukotriene A4 epoxide hydrolase. Eosinophils, mast cells, and alveolar macrophages use the enzyme leukotriene C4 synthase to conjugate glutathione with LTA₄ to make LTC₄, which is transported outside the cell, where a glutamic acid moiety is removed from it to make LTD₄. The leukotriene LTD₄ is then cleaved by dipeptidases to make LTE₄. The leukotrienes LTC₄, LTD₄ and LTE₄ all contain cysteine and are collectively known as the cysteinyl leukotrienes.

[edit] References

1. ^ Cyberlipid Center. Prostanoids. Retrieved on June 1, 2006.
2. ^ University of Kansas Medical Center (2004). Eicosanoids and Inflammation. Retrieved on 2007-01-05.
3. ^ Soberman, Roy J. and Christmas, Peter (2003). "The organization and consequences of eicosanoid signaling". J. Clin. Invest 111: 1107–1113. doi:10.1172/JCI200318338. 
4. ^ Cyrus, Tillmann (June 1999). "Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E–deficient mice". J Clin Invest 103: 1597–1604n. doi:10.1172/JCI5897. 
5. ^ Schewe T. (2002 Mar-Apr). "15-lipoxygenase-1: a prooxidant enzyme". Biol Chem. 383 (3-4). 
6. ^ Funk, Colin D. (30 November 2001). "Prostaglandins and Leukotrienes: Advances in Eicosanoid Biology". Science 294 (5548): 1871–1875. doi:10.1126/science.294.5548.1871.