Arachidonate 5-lipoxygenase

arachidonate 5-lipoxygenase
Identifiers
EC number	1.13.11.34
CAS number	Template:CAS
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
Search PMC articles PubMed articles NCBI proteins

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

Substrates and products

Polyunsaturated fatty acid substrates and products of 5-LO include:

• 5-LO metabolizes the omega-6 fatty acid, Arachidonic acid (AA), to 5-hydroperoxyeicosatetraenoic acids (5-HpETE) which is then converted to the physiologically and pathologically important products, 5-hydroxyeicosatetraenoic acid (5-HETE), 5-oxo-eicosatetraenoic acid (5-oxo-ETE), and the 4-series leukotrienes (LTB4, LTC4, LTD4, and LTE4). LTB4 and 5-HETE contribute to the innate immune response as leukocyte chemotactic factors, i.e. they recruit circulating blood neutrophils and monccytes to sites of microbial invasions, tissue injury, and foreign bodies. They thereby contributing to inflammatory responses, host defense, and subsequent tissue repair as well as to pathological inflammatory diseases (see 5-HETE and LTB4). 5-Oxo-ETE may contribute to physiological allergic reactions as well as to pathological allergic diseases as a chemotactic factor for circulating blood eosinophils to recruit these cells to sites of allergic reactivity in lung and other tissues (see 5-oxo-eicosatetraenoic acid). LTC4, LTD4, and LTE4 contribute to allergic airways reactions by contracting these airways (see LTC4, LTD4, and LTE4).
• 5-LO metabolizes the omega-6 fatty acid, Mead acid (i.e. 5Z,8Z,11Z-eicosatrienoic acid), to 3-series analogs viz., 5(S)-hydroxy-6E,8Z,11Z-eicosatrienoic acid (5-HETrE), 5-oxo-6,8,11-eicosatrienoic acid (5-oxo-ETrE), LTA3, and LTC3; since LTA3 inhibits LTA hydrolase, mead acid metabolizing cells produce relatively little LTB3 and are blocked from metabolizing arachidonic acid to LTB4. 5-oxo-ETrE is almost as potent as 5-oxo-ETE as an eosinophil chemotactic factor.
• 5-LO metabolizes the omega-3 fatty acid, Eicosapentaenoic acid (EPA), to 5-hydroxyeicosatentaenoic acid which is then converted to 5-series products that are analogous to the arachidonic acid products viz., 5-hydroxy-eioxapentaenoic acid (5-HEPE), 5-oxo-eiocosapentaenoic acid (5-oxo-HEPE), and the 5-series leukotrienes, LTB5, LTC5, LTD5, and LTE5. In general, these eicosapentaenoic acid metabolites are less potent in stimulating cells and tissues than their arachidonic acid metabolites.
• Certain other polyunsaturated fatty acids such as DGLA and linoleic acid inhibit 5-LO from metabolizing arachidonic acid.

Function

5-LO catalyzes oxidation of AA at the 5-position to yield 5-HpETE. 5-LO then converts 5-HpETE to 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 eosinophils and basophils, and a possible mediator of allergic reactions in humans.

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

Eicosanoid synthesis.

Two other lipoxygenases, 12-LO and 15-LO, act at the 12- and 15-positions, metabolizing arachidonic acid 12- and 15-hydroperoxy intermediates which are then further metabolized to bioactive products including 12-hydroxyeicosatetraenoic acid (12-HETE), 15-hydroxyicosatetraenoic acid (15-HETE), lipoxins, and Hepoxilins.

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

Main article: Arachidonate 5-lipoxygenase inhibitor

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.

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

Activation

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

Interactions

Arachidonate 5-lipoxygenase has been shown to interact with:

• COTL1, and
• Grb2.

External links

• Arachidonate 5-Lipoxygenase at the US National Library of Medicine Medical Subject Headings (MeSH)