Arachidonate 5-lipoxygenase

Arachidonate 5-lipoxygenase (5-lipoxygenase, 5-LO or Alox5) is a human enzyme, member of the lipoxygenase family. It transforms EFAs into leukotrienes and is a current target for pharmaceutical intervention in a number of diseases.

Substrates and products
EFA substrates and leukotriene products of 5-LO include:
 * Arachidonic acid (AA) yields the 4-series leukotrienes (LTB4, LTC4, LTD4, LTE4 &mdash; generally proinflammatory)
 * Eicosapentaenoic acid (EPA) yields the 5-series (LTB5, LTC5, LTD5, LTE5 &mdash; antiinflammatory)
 * Gamma-linolenic acid (GLA via the DGLA intermediary) yields no leukotrienes, but inhibits the conversion of AA.

Functions
5-LO catalyzes oxidation of AA at the 5-position to yield 5-hydroperoxyeicosatetraenoic acid (5-HPETE). 5-LO then converts 5-HPETE to leukotriene A4.



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 12-hydroxyeicosatetraenoic acid (12-HETE) and to the lipoxins, respectively.

Clinical significance
5-LO is a target for pharmaceutical intervention in CAD. Some people with variant 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 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 asthma, 5-LO inhibitors were developed as asthma treatments. The only 5-LO inhibitor currently licensed for human use in asthma is Zileuton.

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

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