Arachidonate 5-lipoxygenase

Arachidonate 5-lipoxygenase, also known as 5-lipoxygenase, 5-LOX or 5-LO, is an is_associated_with::enzyme that in humans is encoded by the ALOX5 is_associated_with::gene. Arachidonate 5-lipoxygenase is a member of the is_associated_with::lipoxygenase family of enzymes. It transforms EFAs into is_associated_with::leukotrienes and is a current target for pharmaceutical intervention in a number of diseases.

Substrates and products
EFA substrates and products of 5-LO include:
 * is_associated_with::Arachidonic acid (AA) yields 5-hydroperoxyeicosatetraenoic acids (5-HpETE), 5-hydroxyeicosatetraenoic acids (5-HETE), 5-oxo-eicosatetraenoate (5-oxo-ETE), and the 4-series leukotrienes (is_associated_with::LTB4, is_associated_with::LTC4, is_associated_with::LTD4, is_associated_with::LTE4).
 * is_associated_with::Eicosapentaenoic acid (EPA) yields the 5-series (LTB5, LTC5, LTD5, LTE5).
 * is_associated_with::Gamma-linolenic acid (GLA via the DGLA intermediary) yields no leukotrienes, but inhibits the conversion of AA.

Function
5-LO catalyzes oxidation of AA at the 5-position to yield 5-HpETE. 5-LO then converts 5-HpETE to is_associated_with::leukotriene A4.

As well as being intermediates in the formation of leukotrienes, hydroperoxides are released from lipoxygenase enzymes. These hydroperoxides are rapidly reduced to their corresponding hydroxy- eicosatetraenoates which may then be further metabolize to active products. 5-LO releases 5-HpETE) which can be further metabolized to 5-oxo-ETE, a potent stimulator of cells involved in allergic reactions such as is_associated_with::eosinophils and is_associated_with::basophils, and a possible mediator of allergic reactions in humans.

Recently, oxidized lipid products of 5-LO have been measured in membranes of is_associated_with::neutrophils in the form of esterified-5-HETE phospholipids. These novel products have biological activities including inhibition of is_associated_with::neutrophil extracellular traps.



Two other lipoxygenases, 12-LO and 15-LO, act at the 12- and 15-positions, yielding 12- and 15-HPETE. These pathways lead to the leukotriene is_associated_with::12-hydroxyeicosatetraenoic acid (12-HETE) and to the is_associated_with::lipoxins, respectively.

Clinical significance
5-LO is a target for pharmaceutical intervention in CAD. Some people with variant is_associated_with::alleles for 5-LO are at elevated risk for CAD. 5-LO is expressed in brain cells and may participate in neuropathologic processes.

Mutations in the promoter region of this gene lead to a diminished response to antileukotriene drugs used in the treatment of asthma and may also be associated with is_associated_with::atherosclerosis and several cancers. Alternatively spliced transcript variants have been observed, but their full-length nature has not been determined.

5-LO inhibitors
As leukotrienes are important causes of pathological symptoms in is_associated_with::asthma, 5-LO inhibitors were developed as asthma treatments. The only 5-LO inhibitor currently licensed for human use in asthma is is_associated_with::zileuton.

is_associated_with::Minocycline, although primarily a is_associated_with::tetracycline antibiotic, is also a 5-LO inhibitor. It may therefore be used as a is_associated_with::DMARD-medication in mild is_associated_with::rheumatoid arthritis and other is_associated_with::rheumatic conditions.

is_associated_with::Hyperforin, an active constituent of the herb St John's wort, is a highly potent 5-LO inhibitor. Another natural product, is_associated_with::indirubin-3'-monoxime, was also described as selective 5-LO inhibitor effective in a range of cell-free and cell-based models. In addition, is_associated_with::curcumin, a constituent of is_associated_with::turmeric, is a 5-LO inhibitor is_associated_with::in vitro.

Activation
5-LO is activated by is_associated_with::5-lipoxygenase activating protein (FLAP).

Interactions
Arachidonate 5-lipoxygenase has been shown to interact with:
 * is_associated_with::COTL1, and
 * is_associated_with::Grb2.