Arachidonate 5-lipoxygenase

It transforms essential fatty acids (EFA) substrates into leukotrienes as well as a wide range of other biologically active products.

[2][3] Up-regulation of ALOX5 may occur during the maturation of leukocytes and in human neutrophils treated with granulocyte macrophage colony-stimulating factor and then stimulated with physiological agents.

Sub-human mammalian Alox5 enzymes like those in rodents appear to have, at least in general, similar structures, distributions, activities, and functions as human ALOX5.

These events, along with rises in cytosolic Ca2+ levels, which promote the translocation of ALOX5 form the cytoplasm and nucleoplasm to the cited membranes, are induced by cell stimulation such as that caused by chemotactic factors on leukocytes.

Based on in vitro studies, this protein binding serves to stabilize ALOX5 by acting as a chaperone (protein) or scaffold, thereby averting the enzyme's inactivation to promote its metabolic activity; depending on circumstance such as the presence of phospholipids and levels of ambient Ca2+, this binding also alters the relative levels of hydroperoxy versus epoxide (see arachidonic acid section below) products made by ALOX5.

LTB4, 5-HETE, and 5-oxo-ETE may contribute to the innate immune response as leukocyte chemotactic factors, i.e. they recruit and further activate circulating blood neutrophils and monocytes to sites of microbial invasion, tissue injury, and foreign bodies.

[3] Certain of these peptide-leukotrienes have been shown to promote the growth of cultured human breast cancer and chronic lymphocytic leukemia cell lines thereby suggesting that ALOX5 may contribute to the progression of these diseases.

[23][24] The D series resolvins (i.e. RvD1, RvD2, RvD3, RvD4, RvD5, RvD6, AT-RVD1, AT-RVD2, AT-RVD3, AT-RVD4, AT-RVD5, and AT-RVD6) are specialized pro-resolving mediators that contribute to the resolution of inflammation, promote tissue healing, and reduce the perception of inflammation-based pain.

This may be a reflection of the array of metabolites made by the Alox5 enzyme some of which possess opposing activities like the pro-inflammatory chemotactic factors and the anti-inflammatory specialized pro-resolving mediators.

Alox5 gene knockout mice are more susceptible to the development and pathological complications of experimental infection with Klebsiella pneumoniae, Borrelia burgdorferi, and Paracoccidioides brasiliensis.

These studies indicate that Alox5 can serve a protective function presumably by generating metabolites such as chemotactic factors that mobilize the innate immunity system.

However, the suppression of inflammation appears also to be a function of Alox5, presumably by contributing to the production of anti-inflammatory specialized pro-resolving mediators (SPMs), at least in certain rodent inflammation-based model systems.

These genetic studies allow that ALOX5 along with the chemotactic factors and SPMs that they contribute to making may play similar opposing pro-inflammatory and anti-inflammatory functions in humans.

[8][31][32] ALOX5 contributes to the development and progression of allergy and allergic inflammation reactions and diseases such as: This activity reflects its formation of a) LTC4, LTD4, and LTE4 which promote vascular permeability, contract airways smooth muscle, and otherwise perturb these tissues and b) LTB4 and possibly 5-oxo-ETE which are chemotactic factors for, and activators of, the cell type promoting such reactions, the eosinophil.

[8][14] 5-Oxo-ETE and, to a lesser extent, 5S-HETE, also act synergistically with another pro-allergic mediator, platelet-activating factor, to stimulate and otherwise activate eosinophils.

Zileuton has shown some beneficial effects in clinical trials for the treatment of rheumatoid arthritis, inflammatory bowel disease, and psoriasis.

Flavocoxid has been approved for use as a medical food in the United States since 2004 and is available by prescription for use in chronic osteoarthritis in tablets of 500 mg under the commercial name Limbrel.

[40] Setileuton (MK-0633) has completed a Phase II clinical trial for the treatment of asthma, chronic obstructive lung disease, and atherosclerosis (NCT00404313, NCT00418613, and NCT00421278, respectively).

[43] Indirubin-3'-monoxime, a derivative of the naturally occurring alkaloid, indirubin, is also described as selective ALOX5 inhibitor effective in a range of cell-free and cell-based model systems.

Furthermore, blockers of LTC4, LTD4, and LTE4 synthesis (i.e. ALOX5 inhibitors) as well as of LTC4 and LTD4 receptor antagonists have proven inferior to corticosteroids as single drug therapy for persistent asthma, particularly in patients with airway obstruction.

Consequently, a given abnormality in the expression or activity of ALOX5 due to variations in its gene may promote or suppress inflammation depending on the relative roles these opposing metabolites have in regulating the particular type of reaction examined.

Homozygous variants for this five repeat promoter region in a study of 624 asthmatic children in Ankara, Turkey were much more likely to have severe asthma.

[50] These data suggest that ALOX5 may contribute to dampening the severity of asthma, possibly by metabolizing PUFA to specialized pro-resolving mediators.

[51] Single nucleotide polymorphism differences in the genes that promote ALOX5 activity (i.e. 5-lipoxygenase-activating protein), metabolize the initial product of ALOX5, 5S-HpETE, to LTB4 (i.e. leukotriene-A4 hydrolase), or are the cellular receptors responsible for mediating the cellular responses to the down-stream ALOX products LTC4 and LTD4 (i.e. CYSLTR1 and CYSLTR2) have been associated with the presence of asthma in single population studies.

These studies suggest genetic variants may play a role, albeit a relatively minor one, in the overall susceptibility to allergic asthma.

These have been recently classified into 5 groups 3 of which are not caused by a classical immune mechanism and are relevant to the function of ALOX5: 1) NSAIDs-exacerbated respiratory disease (NERD), i.e. symptoms of bronchial airways obstruction, shortness of breath, and/or nasal congestion/rhinorrhea occurring shortly after NSAID ingestion in patients with a history of asthma and/or rhinosinusitis; 2) NSAIDs-exacerbated cutaneous disease (NECD), i.e. wheal responses and/or angioedema responses occurring shortly after NSAID ingestion in patients with a history of chronic urticaria; and 3) NSAIDs-induced urticaria/angioedema (NIUA) (i.e. wheals and/or angioedema symptoms occurring shortly after NSAID ingestion in patients with no history of chronic urticaria).

[33] Bearers of two variations in the predominant five tandem repeat Sp1 binding motif (GGGCCGG) of the ALOX5 gene promoter in 470 subjects (non-Hispanic whites, 55.1%; Hispanics, 29.6%; Asian or Pacific Islander, 7.7&; African Americans, 5.3%, and others, 2.3%) were positively associated with the severity of atherosclerosis, as judged by carotid intima–media thickness measurements.