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Arachidonate 5-lipoxygenase
Arachidonate 5-lipoxygenase
Arachidonate 5-lipoxygenase
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arachidonate 5-lipoxygenase
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Aliases5-lipoxygenase
External IDsGeneCards: [1]; OMA:- orthologs
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arachidonate 5-lipoxygenase
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EC no.1.13.11.34
CAS no.80619-02-9[permanent dead link]
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Arachidonate 5-lipoxygenase, also known as ALOX5, 5-lipoxygenase, 5-LOX, or 5-LO, is a non-heme iron-containing enzyme (EC 1.13.11.34) that in humans is encoded by the ALOX5 gene.[1] Arachidonate 5-lipoxygenase is a member of the lipoxygenase family of enzymes. It transforms essential fatty acids (EFA) substrates into leukotrienes as well as a wide range of other biologically active products. ALOX5 is a current target for pharmaceutical intervention in a number of diseases.

Gene

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The ALOX5 gene, which occupies 71.9 kilobase pairs (kb) on chromosome 10 (all other human lipoxygenases are clustered together on chromosome 17), is composed of 14 exons divided by 13 introns encoding the mature 78 kilodalton (kDa) ALOX5 protein consisting of 673 amino acids. The gene promoter region of ALOX5 contains 8 GC boxes but lacks TATA boxes or CAT boxes and thus resembles the gene promoters of typical housekeeping genes. Five of the 8 GC boxes are arranged in tandem and are recognized by the transcription factors Sp1 and Egr-1. A novel Sp1-binding site occurs close to the major transcription start site (position – 65); a GC-rich core region including the Sp1/Egr-1 sites may be critical for basal 5-LO promoter activity.[2]

Expression

[edit]

Cells primarily involved in regulating inflammation, allergy, and other immune responses, e.g. neutrophils, eosinophils, basophils, monocytes, macrophages, mast cells, dendritic cells, and B-lymphocytes express ALOX5. Platelets, T cells, and erythrocytes are ALOX5-negative. In skin, Langerhans cells strongly express ALOX5. Fibroblasts, smooth muscle cells and endothelial cells express low levels of ALOX5.[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.

Aberrant expression of LOX5 is seen in various types of human cancer tumors in vivo as well as in various types of human cancer cell lines in vitro; these tumors and cell lines include those of the pancreas, prostate and colon. ALOX5 products, particularly 5-hydroxyeicosatetraenoic acid and 5-oxo-eicosatetraenoic acid, promote the proliferation of these ALOX5 aberrantly expressing tumor cell lines suggesting that ALOX5 acts as a pro-malignancy factor for them and by extension their parent tumors.[2]

Studies with cultured human cells have found that there are a large number of ALOX5 mRNA splice variants due to alternative splicing. The physiological and/or pathological consequences of this slicing has yet to be defined. In one study, however, human brain tumors were shown to express three mRNA splice variants (2.7, 3.1, and 6.4 kb) in addition to the full 8.6 lb species; the abundance of the variants correlated with the malignancy of these tumors suggesting that they may play a role in the development of these tumors.[2]

Biochemistry

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Human ALOX5 is a soluble, monomeric protein consisting of 673 amino acids with a molecular weight of ~78 kDa. Structurally, ALOX5 possesses:[3][4]

  • A C-terminal catalytic domain (residues 126–673)
  • An N-terminal C2-like domain which promotes its binding to ligand substrates, Ca2+, cellular phospholipid membranes, Coactin-like protein (COL1), and Dicer protein
  • A PLAT domain within its C2-like domain; this domain, by analogy to other PLAT domain-bearing proteins, may serve as a mobile lid over ALOX5's substrate-binding site
  • An adenosine triphosphate (ATP) binding site; ATP is crucial for ALOX5's metabolic activity
  • A proline-rich region (residues 566–577), sometimes termed a SH3-binding domain, which promotes its binding to proteins with SH3 domains such as Grb2 and may thereby link the enzyme's regulation to tyrosine kinase receptors.

The enzyme possesses two catalytic activities as illustrated by its metabolism of arachidonic acid. ALOX5's dioxygenase activity adds a hydroperoxyl (i.e. HO2) residue to arachidonic acid (i.e. 5Z,8Z,11Z,14Z-eicosatetraenoic acid) at carbon 5 of its 1,4 diene group (i.e. its 5Z,8Z double bonds) to form 5(S)-hydroperoxy-6E,8Z,11Z,14Z-eicosatetraenoic acid (i.e. 5S-HpETE).[5] The 5S-HpETE intermediate may then be released by the enzyme and rapidly reduced by cellular glutathione peroxidases to its corresponding alcohol, 5(S)-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid (i.e. 5-HETE), or, alternatively, further metabolized by ALOX5's epoxidase (also termed LTA4 synthase) activity which converts 5S-HpETE to its epoxide, 5S,6S-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid (i.e. LTA4).[6] LTA4 is then acted on by a separate, soluble enzyme, leukotriene-A4 hydrolase, to form the dihydroxyl product, leukotriene B4 (LTB4, i.e. 5S,12R-dihydroxy-5S,6Z,8E,10E,12R,14Z-eicosatetraenoic acid) or by either LTC4 synthase or microsomal glutathione S-transferase 2 (MGST2), which bind the sulfur of cysteine's thio (i.e. SH) residue in the tripeptide glutamate-cysteine-glycine to carbon 6 of LTA4 thereby forming LTC4 (i.e. 5S-hydroxy,6R-(S-glutathionyl)-7E,9E,11Z,14Z-eicosatetraenoic acid). The Glu and Gly residues of LTC4 may be removed step-wise by gamma-glutamyltransferase and a dipeptidase to form sequentially LTD4 and LTE4.[4][7] To varying extents, the other PUFA substrates of ALOX5 follow similar metabolic pathways to form analogous products.

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. Hence, model Alox5 studies in rodents appear to be valuable for defining the function of ALOX5 in humans (see Lipoxygenase § Mouse lipoxygenases).

Regulation

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ALOX5 exists primarily in the cytoplasm and nucleoplasm of cells. Upon cell stimulation, ALOX5: a) may be phosphorylated on serine 663, 523, and/or 271 by mitogen-activated protein kinases, S6 kinase, protein kinase A (PKA), protein kinase C, Cdc2, and/or a Ca2+/calmodulin-dependent protein kinase; b) moves to bind with phospholipids in the nuclear membrane and, probably, endoplasmic reticulum membrane; c) is able to accept substrate fatty acids presented to it by the 5-lipoxygenase-activating protein (FLAP) which is embedded in these membranes; and d) thereby becomes suited for high metabolic activity. 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. Rises in cytosolic Ca2+, ALOX5's movement to membranes, and ALOX5's interaction with FLAP are critical to the physiological activation of the enzyme.[3] Serine 271 and 663 phosphorylations do not appear to alter ALOX5's activity. Serine 523 phosphorylation (which is conducted by PKA) totally inactivates the enzyme and prevents its nuclear localization; stimuli which cause cells to activate PKA can thereby block production of ALOX5 metabolites.[4][8]

In addition to its activation, ALOX5 must gain access to its polyunsaturated fatty acid (PUFA) substrates, which commonly are bound in an ester linkage to the sn2 position of membrane phospholipids, in order to form biologically active products. This is accomplished by a large family of phospholipase A2 (PLA2) enzymes. The cytosolic PLA2 set (i.e. cPLA2s) of PLA2 enzymes (see Phospholipase A2 § Cytosolic phospholipases A2 (cPLA2)) in particular mediates many instances of stimulus-induced release of PUFA in inflammatory cells. For example, chemotactic factors stimulate human neutrophils to raise cytosolic Ca2+ which triggers cPLA2s, particularly the α isoform (cPLA2α), to move from its normal residence in the cytosol to cellular membranes. This chemotactic factor stimulation concurrently causes the activation of mitogen-activated protein kinases (MAPK) which in turn stimulates the activity of cPLA2α by phosphorylating it on ser-505 (other cell types may activate this or other cPLA2 isoforms using other kinases which phosphorylate them on different serine residues). These two events allow cPLA2s to release PUFA esterified to membrane phospholipids to FLAP which then presents them to ALOX5 for their metabolism.[9][10]

Other factors are known to regulate ALOX5 activity in vitro but have not been fully integrated into its physiological activation during cell stimulation. ALOX5 binds with the F actin-binding protein, coactin-like protein. 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.[3][4] The binding of ALOX5 to membranes as well as its interaction with FLAP likewise cause the enzyme to alter its relative levels of hydroperoxy versus epoxide production, in these cases favoring the production of the epoxide products.[4] The presence of certain diacylglycerols such as 1-oleoyl-2-acetyl-sn-glycerol, 1-hexadecyl-2-acetyl-sn-glycerol, and 1-O-hexadecyl-2-acetyl-sn-glycerol, and 1,2-dioctanoyl-sn-glycerol but not 1-stearoyl-2-arachidonyl-sn-glycerol increase the catalytic activity of ALOX5 in vitro.[4]

Substrates, metabolites, and metabolite activities

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ALOX5 metabolizes various omega-3 and omega-6 PUFA to a wide range of products with varying and sometimes opposing biological activities. A list of these substrates along with their principal metabolites and metabolite activities follows.

Arachidonic acid

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ALOX5 metabolizes the omega-6 fatty acid, arachidonic acid (AA, i.e. 5Z,8Z,11Z,14Z-eicosatetraenoic acid), to 5-hydroperoxyeicosatetraenoic acid (5-HpETE) which is then rapidly converted to physiologically and pathologically important products. Ubiquitous cellular glutathione peroxidases (GPXs) reduce 5-HpETE to 5-hydroxyeicosatetraenoic acid (5-HETE); 5-HETE may be further metabolized by 5-hydroxyeicosanoid dehydrogenase (5-HEDH) to 5-oxo-eicosatetraenoic acid (5-oxo-ETE). Alternatively, the intrinsic activity of ALOX5 may convert 5-HpETE to its 5,6 epoxide, leukotriene A4 LTA4, which is then either rapidly converted to leukotriene B4 (LTB4) by leukotriene-A4 hydrolase (LTA4H) or to leukotriene C4 (LTC4) by LTC4 synthase (LTC4S); LTC4 exits its cells of origin through the MRP1 transporter (ABCC1) and is rapidly converted to LTD4 and then to LTE4) by cell surface-attached gamma-glutamyltransferase and dipeptidase peptidase enzymes. In another pathway, ALOX5 may act in series with a second lipoxygenase enzyme, ALOX15, to metabolize AA to lipoxin A4 (LxA4) and LxB4 (see Specialized pro-resolving mediators § Lipoxins).[3][11][12][13] GPXs, 5-HEDH, LTA4H, LTC4S, ABCC1, and cell surface peptidases may act similarly on the ALOX5-derived metabolites of other PUFA.

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. When produced in excess, however, they may contribute to a wide range of pathological inflammatory responses (5-HETE and LTB4). 5-Oxo-ETE is a particularly potent chemotactic factor for and activator of eosinophils and may thereby contribute to eosinophil-based allergic reactions and diseases.[4][14] These metabolites may also contribute to the progression of certain cancers such as those of the prostate, breast, lung, ovary, and pancreas. ALOX5 may be overexpressed in some of these cancers; 5-Oxo-ETE and to a lesser extent 5-HETE stimulate human cell lines derived from these cancers to proliferate; and the pharmacological inhibition of ALOX5 in these human cell lines causes them to die by entering apoptosis.[14][15][16][17][18] ALOX5 and its LTB4 metabolite as well as this metabolite's BLT1 and BLT2 receptors have also been shown to promote the growth of various types of human cancer cell lines in culture.[19][20]

LTC4, LTD4, and LTE4 contribute to allergic airways reactions such as asthma, certain non-allergic hypersensitivity airways reactions, and other lung diseases involving bronchoconstriction by contracting these airways and promoting in these airways inflammation, micro-vascular permeability, and mucus secretion; they likewise contribute to various allergic and non-allergic reactions involving rhinitis, conjunctivitis, and urticaria.[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.[19]

LxA4 and LxB4 are members of the specialized pro-resolving mediators class of polyunsaturated fatty acid metabolites. They form later than the ALOX5-derived chemotactic factors in the inflammatory response and are thought to limit or resolve these responses by, for example, inhibiting the entry of circulating leukocytes into inflamed tissues, inhibiting the pro-inflammatory action of the leukocytes, promoting leukocytes to exit from inflammatory sites, and stimulating leukocyte apoptosis (see Specialized pro-resolving mediators and Lipoxin).[11]

Mead acid

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Mead acid (i.e. 5Z,8Z,11Z-eicosatrienoic acid) is identical to AA except that has a single rather than double bond between its 14 and 15 carbon. ALOX5 metabolizes mead acid to 3-series (i.e. containing 3 double bonds) analogs of its 4-series AA metabolites 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. On the other hand, 5-oxo-ETrE is almost as potent as 5-oxo-ETE as an eosinophil chemotactic factor and may thereby contribute to the development of physiological and pathological allergic responses.[12] Presumably, the same metabolic pathways that follow ALOX5 in metabolizing arachidonic acid to the 4-series metabolites likewise act on mead acid to form these products.

Eicosapentaenoic acid

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ALOX5 metabolizes the omega-3 fatty acid, eicosapentaenoic acid (EPA, i.e. 4Z,8Z,11Z,14Z,17Z-eiosapentaenoic acid), to 5-hydroperoxy-eicosapentaenoic acid which is then converted to 5-series products that are structurally analogous to their arachidonic acid counterparts viz., 5-hydroxy-eicosapentaenoic acid (5-HEPE), 5-oxo-eiocosapentaenoic acid (5-oxo-HEPE), LTB5, LTC5, LTD5, and LTE5.[4][21] Presumably, the same metabolic pathways that follow ALOX5 in metabolizing arachidonic acid to the 4-series metabolites likewise act on EPA to form these 5-series products. ALOX5 also cooperates with other lipoxygenase, cyclooxygenase, or cytochrome P450 enzymes in serial metabolic pathways to metabolize EPA to resolvins of the E series (see Specialized pro-resolving mediators § EPA-derived resolvins for further details on this metabolism) viz., resolvin E1 (RvE1) and RvE2.[22][23]

5-HEPE, 5-oxo-HEPE, LTB5, LTC5, LTD5, and LTE5 are generally less potent in stimulating cells and tissues than their arachidonic acid-derived counterparts; since their production is associated with reduced production of their arachidonic acid-derived counterparts, they may indirectly serve to reduce the pro-inflammatory and pro-allergic activities of their arachidonic acid-derived counterparts.[4][21] RvE1 and ReV2 are specialized pro-resolving mediators that contribute to the resolution of inflammation and other reactions.[23]

Docosahexaenoic acid

[edit]

ALOX5 acts in series with ALOX15 to metabolize the omega 3 fatty acid, docosahexaenoic acid (DHA, i.e. 4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid), to D series resolvins (see Specialized pro-resolving mediators § DHA-derived resolvins for further details on this metabolism).[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.[23][24]

Transgenic studies

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Studies in model animal systems that delete or overexpress the Alox5 gene have given seemingly paradoxical results. In mice, for example, Alox5 overexpression may decrease the damage caused by some types yet increase the damage caused by other types of invasive pathogens. 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 and presumably human ALOX5 functions may vary widely depending on: the agents stimulating their activity; the types of metabolites that they form; the specific tissues responding to these metabolites; the times (e.g. early versus delayed) at which observations are made; and very likely various other factors.

Alox5 gene knockout mice are more susceptible to the development and pathological complications of experimental infection with Klebsiella pneumoniae, Borrelia burgdorferi, and Paracoccidioides brasiliensis.[8][25] In a model of cecum perforation-induced sepsis, ALOX5 gene knockout mice exhibited a decrease in the number of neutrophils and an increase in the number of bacteria that accumulated in their peritoneum.[26] On the other hand, ALOX5 gene knockout mice demonstrate an enhanced resistance and lessened pathology to Brucella abortus infection[27] and, at least in its acute phase, Trypanosoma cruzi infection.[28] Furthermore, Alox5-null mice exhibit a worsened inflammatory component, failure to resolve inflammation-related responses, and decreased survival in experimental models of respiratory syncytial virus disease, Lyme disease, Toxoplasma gondii disease, and corneal injury. 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.[22][29]

Alox5 gene knockout mice exhibit an increase in the lung tumor volume and liver metastasis of Lewis lung carcinoma cells that were directly implanted into their lungs; this result differs from many in vitro studies which implicated human ALOX5 along with certain of its metabolites with promoting cancer cell growth in that it finds that mouse Alox5 and, perhaps, certain of its metabolites inhibit cancer cell growth. Studies in this model suggest that Alox5, acting through one or more of its metabolites, reduces growth and progression of the Lewis carcinoma by recruiting cancer-inhibiting CD4+ T helper cells and CD8+ T cytotoxic T cells to the sites of implantation.[30] This striking difference between human in vitro and mouse in vivo studies may reflect species differences, in vitro versus in vivo differences, or cancer cell type differences in the function of ALOX5/Alox5.

Clinical significance

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Inflammation

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Studies implicate ALOX5 in contributing to innate immunity by contributing to the mounting inflammatory responses to a wide range of diseases:

however, ALOX5 also contributes to the development and progression of excessive and chronic inflammatory responses such as:

(see Inflammation § Disorders).

These dual functions probably reflect ALOX5's ability to form the: a) potent chemotactic factor, LTB4, and possibly also weaker chemotactic factor, 5S-HETE, which serve to attract and otherwise activate inflammation-inducing cells such as circulating leukocytes and tissue macrophages and dendritic cells and b) lipoxin and resolvin subfamily of SPMs which tend to inhibit these cells as well as the overall inflammatory responses.[8][31][32]

Allergy

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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.[14][33][34][35]

Hypersensitivity reactions

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ALOX5 contributes to non-allergic NSAID hypersensitivity reactions of the respiratory system and skin such as:

It may also contribute to hypersensitivity responses of the respiratory system to cold air and possibly even alcohol beverages. These pathological responses likely involve the same ALOX5-formed metabolites as those promoting allergic reactions.[13][8][36]

ALOX5-inhibiting drugs

[edit]
Main article: Arachidonate 5-lipoxygenase inhibitor

The tissue, animal model, and animal and human genetic studies cited above implicate ALOX5 in a wide range of diseases:

(see Inflammation § Disorders)

However, clinical use of drugs that inhibit ALOX5 to treat any of these diseases has been successful with only Zileuton along with its controlled released preparation, Zileuton CR.

Zileuton is approved in the US for the prophylaxis and chronic treatment of allergic asthma; it is also used to treat chronic non-allergic reactions such as NSAID-induced non-allergic lung, nose, and conjunctiva reactions as well as exercise-induced asthma. Zileuton has shown some beneficial effects in clinical trials for the treatment of rheumatoid arthritis, inflammatory bowel disease, and psoriasis.[8][37] Zileuton is currently undergoing a phase II study for the treatment of acne vulgaris (mild-to-moderate inflammatory facial acne) and a phase I study (see Clinical trial § Phases) combining it with imatinib for treating chronic myeloid leukemia.[38][39] Zyleuton and zileuton CR cause elevations in liver enzymes in 2% of patients; the two drugs are therefore contraindicated in patients with active liver disease or persistent hepatic enzyme elevations greater than three times the upper limit of normal. Hepatic function should be assessed prior to initiating either of these drugs, monthly for the first 3 months, every 2–3 months for the remainder of the first year, and periodically thereafter; zileuton also has a rather unfavorable pharmacological profile (see Zileuton § Contraindications and warnings).[38] Given these deficiencies, other drugs targeting ALOX5 are under study.

Flavocoxid is a proprietary blend of purified plant derived bioflavonoids including Baicalin and Catechins. It inhibits COX-1, COX-2, and ALOX5 in vitro and in animal models. 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. However, in clinical trials serum liver enzyme elevations occurred in up to 10% of patients on flavocoxid therapy although elevations above 3 times the upper limit of normal occurred in only 1-2% of recipients. Since its release, however, there have been several reports of clinically apparent acute liver injury attributed to flavocoxid.[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).[38][41] PF-4191834[42] has completed phase II studies for the treatment of asthma (NCT00723021).[38]

Hyperforin, an active constituent of the herb St John's wort, is active at micromolar concentrations in inhibiting ALOX5.[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.[44] In addition, curcumin, a constituent of turmeric, is a 5-LO inhibitor as defined by in vitro studies of the enzyme.[45]

Acetyl-keto-beta-boswellic acid (AKBA), one of the bioactive boswellic acids found in Boswellia serrata (Indian Frankincense) has been found to inhibit 5-lipoxygenase. Boswellia reduces brain edema in patients irradiated for brain tumor and it's believed to be due to 5-lipoxygenase inhibition.[46][47]

While only one ALOX5-inhibiting drug has proven useful for treating human diseases, other drugs that act down-stream in the ALOX5-initiated pathway are in clinical use. Montelukast, Zafirlukast, and Pranlukast are receptor antagonists for the cysteinyl leukotriene receptor 1 which contributes to mediating the actions of LTC4, LTD4, and LTE4. These drugs are in common use as prophylaxis and chronic treatment of allergic and non-allergic asthma and rhinitis diseases[3] and also may be useful for treating acquired childhood sleep apnea due to adenotonsillar hypertrophy (see Acquired non-inflammatory myopathy § Diet and Trauma Induced Myopathy).[48]

To date, however, neither LTB4 synthesis inhibitors (i.e. blockers of ALOX5 or LTA4 hydrolase) nor inhibitors of LTB4 receptors (BLT1 and BLT2) have turned out to be effective anti-inflammatory drugs. 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. As a second drug added to corticosteroids, leukotriene inhibitors appear inferior to beta2-adrenergic agonist drugs in the treatment of asthma.[49]

Human genetics

[edit]

ALOX5 contributes to the formation of PUFA metabolites that may promote (e.g. the leukotrienes, 5-oxo-ETE) but also to metabolites that inhibit (i.e. lipoxins, resolvins) diseases. 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. Furthermore, the ALOX5-related tissue reactions studied to date are influenced by multiple genetic, environmental, and developmental variables that may influence the consequences of abnormalities in the expression or function of ALOX5. Consequently, abnormalities in the ALOX5 gene may vary with the population and individuals studied.

Allergic asthma

[edit]

The upstream promoter in the human ALOX5 gene commonly possess five GGGCCGG repeats which bind the Sp1 transcription factor and thereby increase the gene's transcription of ALOX5. 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. These variants are associated with reduced levels of ALOX5 as well as reduced production of LTC4 in their eosinophils.[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.[50]

NSAID-induced non-allergic reactions

[edit]

Aspirin and other non-steroidal anti-inflammatory drugs (NSAID) can cause NSAID-exacerbated diseases (N-ERD). 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).[52] The genetic single-nucleotide polymorphism (SNP) variant in the ALOX5 gene, ALOX5-1708 G>A is associated with NSAID-induced asthma in Korean patients and three SNP ALOX5 variants, rs4948672,[53] rs1565096,[54] and rs7894352,[55] are associated with NSAID-induced cutaneous reactions in Spanish patients.[33]

Atherosclerosis

[edit]

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. Variant alleles involved deletions (one or two) or additions (one, two, or three) of Sp1 motifs to the five tandem motifs allele.[56]

See also

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Arachidonate 5-lipoxygenase inhibitor

References

[edit]

Further reading

[edit]
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Arachidonate 5-lipoxygenase

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Arachidonate 5-lipoxygenase (ALOX5), also known as 5-lipoxygenase (5-LO), is a key enzyme in the pathway that catalyzes the initial steps in the biosynthesis of s, potent lipid mediators of derived from (AA). It performs a bifunctional role: first, oxygenating AA at the 5-position to form 5-hydroperoxyeicosatetraenoic acid (5-HPETE), and second, dehydrating 5-HPETE to produce the A4 (LTA4), which serves as a precursor for bioactive leukotrienes such as LTB4 and the cysteinyl leukotrienes (LTC4, LTD4, LTE4). This process is essential for inflammatory responses, including , , and . The enzyme is a monomeric protein of approximately 78 kDa, encoded by the ALOX5 gene on human chromosome 10, consisting of 673 with an N-terminal β-sandwich domain and a C-terminal catalytic domain that coordinates a non-heme iron atom with His-367, His-372, His-550, and the C-terminal carboxylate of Ile-673. Primarily expressed in leukocytes such as neutrophils, , macrophages, and mast cells, 5-LO is predominantly nuclear in resting cells but translocates to the upon cellular , where it associates with the membrane-bound accessory protein FLAP (five-lipoxygenase-activating protein) to facilitate substrate access. Its activity is tightly regulated by calcium ions (Ca²⁺, with of 1-2 μM), ATP, and events at sites like Ser-271, Ser-523, and Ser-663, which modulate translocation, stability, and catalytic efficiency; for instance, ERK-mediated at Ser-271 enhances activity, while PKA inhibits it. Beyond inflammation, 5-LO plays significant roles in various pathologies, including —where cysteinyl leukotrienes contribute to airway hyperresponsiveness—and , with LTB4 promoting recruitment in plaques. It is also implicated in tumorigenesis, being overexpressed in cancers such as pancreatic, , colorectal, and malignancies, where it supports , survival, and through production and β-catenin signaling. Therapeutically, 5-LO inhibitors like zileuton are approved for treatment, blocking synthesis to reduce symptoms, while receptor antagonists such as target downstream effects. Genetic variations in the ALOX5 promoter, such as Sp1-binding site polymorphisms, influence enzyme expression and susceptibility to cardiovascular diseases.

Gene and Structure

Gene Organization

The ALOX5 gene, which encodes arachidonate 5-lipoxygenase, is located on the long arm of human chromosome 10 at cytogenetic band q11.21, spanning approximately 72 kb from position 45,374,216 to 45,446,117 (GRCh38.p14) on the plus strand and comprising 14 exons separated by 13 introns. This supports the production of a 78 kDa protein through precise splicing of the primary transcript. The ALOX5 gene exhibits strong evolutionary conservation across mammals, with high and sequence homology between human and orthologs in species such as (Mus musculus) and (Rattus norvegicus), reflecting its essential role in biosynthesis and inflammatory responses. Intron-exon boundaries are similarly preserved, maintaining the 14-exon structure in and , which underscores the gene's ancient origin traceable to early vertebrates like , where functional analogs show up to 74% identity. The promoter region of ALOX5, located upstream of exon 1, is TATA-less and contains multiple GC-rich motifs, including consensus binding sites for the as variable tandem repeats of the GGGCGG sequence, which facilitate basal and inducible expression in myeloid cells. Additionally, response elements (GREs) are present, enabling regulation by receptors (GR) and contributing to modulation of transcription. Alternative splicing of ALOX5 pre-mRNA generates multiple transcript variants, including at least four isoforms that introduce premature termination codons (PTCs) and are targeted for degradation by nonsense-mediated mRNA decay (NMD). These variants, often arising from or cryptic splice site usage, primarily serve a regulatory function by fine-tuning 5-lipoxygenase mRNA levels in response to cellular stimuli, thereby influencing production without producing functional protein isoforms.

Protein Structure

Arachidonate 5-lipoxygenase (ALOX5), also known as 5-lipoxygenase, is a monomeric enzyme with a molecular weight of approximately 78 kDa, consisting of 674 amino acid residues in humans. The protein features a modular architecture with two principal domains: an N-terminal β-barrel domain (residues 1–114) that resembles a C2-like domain, and a larger C-terminal catalytic domain (residues 121–674) responsible for the lipoxygenation activity. This organization allows for regulatory interactions at the N-terminus and substrate processing at the C-terminus, with the domains connected by a flexible linker that influences overall conformation. The is located within the C-terminal catalytic domain and contains a non-heme iron cofactor essential for . The iron is coordinated by the side chains of three conserved residues (His367, His372, and His550) and the main-chain carboxylate of the C-terminal Ile673, forming the typical iron-binding motif that stabilizes the (Fe²⁺) or ferric (Fe³⁺) state of the iron during the dioxygenation reaction. Structural studies have revealed that perturbations in this coordination, such as , can alter stability and activity. The N-terminal C2-like domain harbors calcium-binding motifs that play a critical role in regulating ALOX5 function through conformational changes. Specifically, two calcium-binding sites are present, each involving loops connecting the β-sheets; key ligating residues include Asn43, Asp44, and Glu46 in one loop, with a (K_d) of approximately 6 μM for Ca²⁺ binding. Calcium coordination induces a hydrophobic exposure in these loops, promoting membrane association—particularly with phosphatidylcholine-containing membranes—and facilitating translocation of ALOX5 to intracellular sites like the , which enhances enzymatic activation. This Ca²⁺-dependent mechanism underscores the domain's role in stimulus-responsive localization without directly participating in catalysis. High-resolution crystal structures have provided detailed insights into ALOX5 architecture. The first apo-structure of a stabilized human ALOX5 variant (with C-terminal modifications for solubility) was determined at 2.4 Å resolution (PDB: 3O8Y), revealing a compact fold with the N-terminal domain capping the catalytic core and the iron site accessible via a substrate channel. A subsequent structure in complex with arachidonic acid (PDB: 3V99) at 2.25 Å resolution captured the enzyme in a conformation mimicking phosphorylation, highlighting how substrate binding repositions helices near the active site to accommodate the fatty acid tail. Earlier homology models, based on the related rabbit 15-lipoxygenase (PDB: 1LOX), predicted the domain arrangement and iron coordination, guiding mutagenesis studies that validated key functional residues. These structural data emphasize the enzyme's dynamic nature, with flexible regions enabling transitions between soluble and membrane-bound states.

Expression and Localization

Tissue and Cellular Expression

Arachidonate 5-lipoxygenase (ALOX5), also known as 5-lipoxygenase, is primarily expressed in various leukocyte populations under basal conditions, including neutrophils, , mast cells, and macrophages, where it plays a key role in biosynthesis. In these cells, mRNA expression levels are notably high in neutrophils and , while medium levels are observed in mast cells and macrophages, as determined by single-cell RNA sequencing (scRNA-seq) and bulk analyses from normal human tissues. ALOX5 is also expressed at low basal levels in airway epithelial cells, contributing to tissue-enhanced expression in lung tissue overall. In non-immune tissues, ALOX5 exhibits lower basal expression. Protein levels are not detected and mRNA levels are very low (NX <5) in brain tissue across multiple regions, based on RNA-seq data from postmortem samples. Similarly, heart tissue shows not detected mRNA expression (NX <1), with no protein detection in cardiomyocytes under steady-state conditions. Spleen, as a lymphoid organ rich in immune cells, displays medium overall mRNA expression (NX 10-50), attributable to the resident leukocyte populations rather than stromal components. Quantitative RNA-seq studies, such as those from the Genotype-Tissue Expression (GTEx) project integrated in the Protein Atlas, confirm these patterns, with normalized expression (NX) values exceeding 50 in granulocytes but below 5 in brain and below 1 in heart samples. Developmentally, ALOX5 expression is upregulated during myeloid differentiation, particularly in the granulocytic lineage. For instance, in HL-60 promyelocytic leukemia cells induced to differentiate into granulocytes, ALOX5 protein levels and activity increase significantly during differentiation, as measured by Western blot and enzymatic assays. This pattern reflects its role in maturing myeloid cells, with basal expression low in hematopoietic stem cells but rising progressively in committed progenitors. Expression can be further modulated by inflammatory stimuli in these cell types.

Subcellular Localization

In resting cells, arachidonate 5-lipoxygenase (ALOX5), also known as 5-lipoxygenase (5-LO), is predominantly localized in the cytosol, particularly in neutrophils and eosinophils, where it exists in a soluble form. However, cell-type variations exist; for instance, in alveolar macrophages and peritoneal neutrophils, ALOX5 is found in the soluble nuclear compartment associated with euchromatin even in the unstimulated state. This distribution positions ALOX5 away from membrane substrates in inactive conditions, preventing untimely leukotriene synthesis. Upon cellular activation, ALOX5 translocates from the cytosol or nucleoplasm to the nuclear envelope, a process essential for its catalytic function in leukotriene biosynthesis. This relocation is dependent on calcium influx, which promotes membrane association (with half-maximal translocation at approximately 50-160 nM calcium ionophore concentrations in neutrophils), and phosphorylation events, such as at serine 271, which enhance nuclear retention by inhibiting exportin-1-mediated export. In activated leukocytes, ALOX5 associates with the perinuclear region, facilitating proximity to arachidonic acid released from nuclear membranes. Immunofluorescence and confocal microscopy studies have visualized these dynamics, demonstrating cytosolic staining in resting blood neutrophils that shifts to colocalization with the nuclear envelope and DNA upon stimulation with calcium ionophores like A23187. Similarly, GFP-tagged ALOX5 constructs in cell lines confirm rapid nuclear import and perinuclear accumulation within minutes of activation. ALOX5 interacts with 5-lipoxygenase-activating protein (FLAP) at the nuclear membrane to anchor and stabilize its position during translocation.

Biochemistry

Catalytic Mechanism

Arachidonate 5-lipoxygenase (ALOX5) catalyzes the dioxygenation of polyunsaturated fatty acids, such as , at the 5-position to form 5-hydroperoxyeicosatetraenoic acid (5-HPETE). This initial step initiates the biosynthesis of leukotrienes and involves the enzyme's bifunctional activity, where it also functions as leukotriene A4 (LTA4) synthase in a subsequent dehydration reaction. The catalytic mechanism proceeds in two distinct steps. First, the enzyme abstracts a hydrogen atom from the C7 position of the substrate, generating a pentadienyl radical intermediate; this is followed by the insertion of molecular oxygen at the C5 position, yielding 5-HPETE with the hydroperoxy group in the (S)-configuration. In the second step, LTA4 synthase activity dehydrates 5-HPETE through abstraction of a hydrogen from C10, leading to the formation of the epoxy leukotriene LTA4 while preserving stereospecificity, including the (S)-configuration at C5 and specific geometry at C12 in intermediate alignments. The active site non-heme iron cofactor cycles between Fe²⁺ and Fe³⁺ states to facilitate these radical-mediated transformations. Kinetic studies indicate a Michaelis constant (Km) for arachidonic acid of approximately 10 μM, reflecting efficient substrate binding under physiological conditions. The maximum velocity (Vmax) is reported as around 2-4 nmol/min/mg protein in purified enzyme preparations, with optimal activity at a pH of about 7.5-8.0. These parameters underscore the enzyme's role in rapid response to inflammatory signals.

Substrates and Products

Arachidonate 5-lipoxygenase (ALOX5), also known as 5-lipoxygenase, primarily catalyzes the oxygenation of arachidonic acid (20:4 n-6) at the carbon-5 position to form (5S)-hydroperoxyeicosatetraenoic acid ((5S)-5-HPETE), an unstable intermediate that undergoes dehydration to yield the epoxide leukotriene A4 (LTA4). This two-step reaction requires the presence of 5-lipoxygenase-activating protein (FLAP) and is the committed step in leukotriene biosynthesis. LTA4 serves as a pivotal branch-point intermediate, which can be enzymatically processed further: it is hydrolyzed by leukotriene A4 hydrolase to produce the dihydroxy leukotriene B4 (LTB4), a potent chemoattractant, or conjugated with glutathione by leukotriene C4 synthase to form leukotriene C4 (LTC4), the precursor to the cysteinyl leukotrienes LTD4 and LTE4, which mediate bronchoconstriction and vascular permeability. In addition to arachidonic acid, ALOX5 accommodates alternative polyunsaturated fatty acid substrates, albeit with varying efficiencies. Eicosapentaenoic acid (EPA, 20:5 n-3), an omega-3 fatty acid, is oxygenated at the 5-position to generate (5S)-5-hydroperoxyeicosapentaenoic acid ((5S)-5-HpEPE), which can be reduced to 5-hydroxyeicosapentaenoic acid (5-HEPE). Similarly, docosahexaenoic acid (DHA, 22:6 n-3) serves as a substrate, primarily yielding (7S)-7-hydroperoxydocosahexaenoic acid ((7S)-7-HpDHA), though minor 5-hydroperoxy products have been observed under certain conditions. Mead acid (20:3 n-9), an n-9 fatty acid that accumulates during essential fatty acid deficiency, is also metabolized by ALOX5 to 5-hydroperoxy-6,8,11-eicosatrienoic acid (5-HpETrE) and its reduced analog 5-hydroxy-6,8,11-eicosatrienoic acid. Recent studies have highlighted ALOX5's role in generating specialized pro-resolving mediators (SPMs) from omega-3 substrates like DHA, contributing to inflammation resolution. These alternative pathways underscore ALOX5's versatility in eicosanoid metabolism beyond pro-inflammatory leukotrienes.

Regulation

Transcriptional Control

The ALOX5 gene promoter is GC-rich and lacks a TATA box or CCAAT box, resembling that of housekeeping genes, with multiple GC boxes serving as key regulatory elements. Basal transcription is primarily driven by the transcription factor Sp1, which binds to these GC boxes; the core promoter region, spanning approximately the first 300 base pairs upstream of the transcription start site, mediates high constitutive activity in leukocytic cell lines such as RAW 264.7 macrophages. Polymorphisms in the tandem Sp1/Egr1 binding sites within the proximal promoter (-176 to -147 bp) can alter transcription factor affinity, reducing reporter gene activity and influencing ALOX5 expression levels associated with conditions like asthma. Epigenetic modifications play a critical role in regulating ALOX5 transcription, particularly through DNA methylation and histone acetylation at the promoter. The promoter is unmethylated in cells expressing high levels of 5-lipoxygenase, such as HL-60 promyelocytes, while methylation correlates with silencing in non-expressing lines like U-937 monocytes, establishing cell-type-specific expression patterns. Histone deacetylase inhibitors, such as trichostatin A, enhance promoter acetylation, increasing recruitment of Sp1/Sp3 and RNA polymerase II to boost transcription up to several-fold in myeloid cells. Inducible expression of ALOX5 occurs in response to inflammatory stimuli, notably lipopolysaccharide (LPS) in human monocytic cells. Treatment with LPS (100 ng/mL) activates the ALOX5 promoter more than twofold in MM6 and THP-1 cells, elevating 5-lipoxygenase mRNA and protein levels while enhancing leukotriene production; this effect involves TLR4 signaling and synergizes with TGF-β to amplify expression up to 54-fold. Phorbol esters like PMA, used to induce monocytic differentiation, similarly upregulate ALOX5 during maturation of precursor cells into functional leukocytes, contributing to heightened inflammatory responses in tissues such as lung and spleen. These changes in transcriptional control underlie tissue-specific variations in 5-lipoxygenase expression during inflammation.

Post-Translational Modifications

Arachidonate 5-lipoxygenase (ALOX5) is subject to multiple post-translational modifications that fine-tune its enzymatic activity, subcellular localization, and protein stability. Phosphorylation at serine 271 (Ser271) by mitogen-activated protein kinase-activated protein kinase 2 (MK2), which acts downstream of p38 mitogen-activated protein kinase (MAPK) pathway, plays a pivotal role in regulating ALOX5 function. This modification, stimulated by arachidonic acid, enhances ALOX5 translocation from the cytosol to the nuclear membrane and boosts its catalytic efficiency in leukotriene production. Mutation of Ser271 to alanine abolishes this phosphorylation, underscoring its specificity and importance for activity modulation. Other phosphorylation sites include Ser-523 and Ser-663. Phosphorylation at Ser-523 by inhibits ALOX5 activity, while phosphorylation at Ser-663 by extracellular signal-regulated kinase 2 (ERK2) enhances catalytic activity and product synthesis. Calcium-dependent binding further governs ALOX5 membrane association. The N-terminal C2-like domain of ALOX5 coordinates calcium ions with high affinity, inducing a conformational shift that enables electrostatic and hydrophobic interactions with phospholipids, such as phosphatidylinositol bisphosphate and phosphatidylcholine, on nuclear and perinuclear membranes. This translocation, triggered by elevated intracellular calcium during cellular activation, positions ALOX5 proximal to its substrates and is essential for efficient oxygenation reactions. ALOX5 protein levels are controlled through ubiquitination and subsequent proteasomal degradation. The E3 ubiquitin ligase TRIM65 mediates K48-linked ubiquitination of ALOX5, marking it for 26S proteasome breakdown and thereby reducing its stability under stress conditions like ischemia-reperfusion injury. Additionally, certain missense variants in ALOX5 promote protein misfolding, accelerating ubiquitination-dependent proteasomal degradation and diminishing enzyme abundance. Interaction with 5-lipoxygenase activating protein (FLAP) represents a key non-covalent post-translational regulatory mechanism. FLAP, an 18-kDa integral membrane protein, facilitates the transfer of arachidonic acid from membrane phospholipids to ALOX5 at the nuclear envelope, enhancing substrate availability without altering ALOX5 covalently. This protein-protein interaction is indispensable for leukotriene synthesis in activated leukocytes and depends on ALOX5's calcium-induced membrane recruitment.

Physiological Roles

Leukotriene Biosynthesis Pathway

Arachidonic acid (AA), released from membrane phospholipids by cytosolic phospholipase A2 (cPLA2), serves as the precursor for multiple eicosanoid pathways, including the leukotriene biosynthesis route initiated by arachidonate 5-lipoxygenase (ALOX5). Upon cellular stimulation, cPLA2 translocates to the nuclear membrane, liberating AA for subsequent oxygenation by ALOX5, which catalyzes the conversion of AA to 5(S)-hydroperoxyeicosatetraenoic acid (5-HPETE) and then to the epoxide intermediate leukotriene A4 (LTA4). This two-step reaction requires calcium-dependent translocation of ALOX5 to the nuclear envelope, where it forms a multi-enzyme complex with cPLA2 and the 5-lipoxygenase-activating protein (FLAP), a transmembrane protein that facilitates AA presentation to ALOX5 and stabilizes the complex. LTA4, the pivotal intermediate, is rapidly metabolized by downstream enzymes: LTA4 hydrolase (LTA4H) hydrolyzes it to leukotriene B4 (LTB4), while leukotriene C4 synthase (LTC4S) conjugates it with glutathione to form leukotriene C4 (LTC4), the precursor to other cysteinyl leukotrienes. FLAP also interacts with LTC4S in this nuclear membrane complex, coordinating leukotriene production efficiency. In comparison, AA metabolism diverges at the initial oxygenation step: the cyclooxygenase (COX) pathway, mediated by COX-1 or COX-2, produces prostaglandin H2 (PGH2) leading to prostaglandins and thromboxanes, while the 12/15-lipoxygenase (12/15-LOX) branch generates hydroxyeicosatetraenoic acids (HETEs) and lipoxins, contrasting the 5-LOX route's focus on LTA4-derived leukotrienes. These parallel branches allow cells to produce distinct eicosanoid profiles based on enzyme expression and stimuli.

Role in Inflammation and Immunity

Arachidonate 5-lipoxygenase (ALOX5) plays a central role in acute inflammation by catalyzing the production of (LTB4), a potent lipid mediator that drives neutrophil chemotaxis and activation. LTB4, generated through the leukotriene biosynthesis pathway initiated by ALOX5, binds to its receptor BLT1 on neutrophils, promoting their directed migration to sites of injury or infection and enhancing their release of reactive oxygen species and pro-inflammatory cytokines. This process amplifies the initial inflammatory response, facilitating rapid recruitment of immune cells to contain pathogens or damaged tissue. In host defense against infections, ALOX5-derived leukotrienes support leukocyte functions essential for pathogen clearance, including neutrophil phagocytosis and eosinophil degranulation. For instance, LTB4 enhances neutrophil-mediated bacterial killing in the lungs, improving microbicidal activity against pathogens like Klebsiella pneumoniae. Eosinophils, which express ALOX5, utilize leukotrienes to release cytotoxic granules, contributing to bacterial containment in mucosal sites, though their role is more prominent in parasitic infections. These mechanisms underscore ALOX5's importance in innate immunity, where leukotriene signaling coordinates early antimicrobial responses. During the resolution phase of inflammation, ALOX5 participates in the biosynthesis of specialized pro-resolving mediators (SPMs) such as lipoxins and resolvins from alternative polyunsaturated fatty acid substrates, which counteract pro-inflammatory signals. These SPMs, formed via transcellular metabolism involving ALOX5, promote anti-inflammatory polarization of macrophages toward an M2 phenotype, enhancing efferocytosis of apoptotic cells and tissue repair. This shift helps terminate inflammation without fibrosis or chronicity. Studies using Alox5 knockout mice demonstrate impaired inflammatory responses, with reduced neutrophil influx in models of acute peritonitis or airway inflammation, leading to diminished chemotaxis but also decreased tissue damage from excessive leukocyte activity. These mice exhibit defective LTB4 production, resulting in slower pathogen clearance in some infections, yet they show protection against overexuberant inflammation in fungal models like cryptococcosis, highlighting ALOX5's dual role in balancing immune activation and resolution.

Pathological Implications

Allergic and Respiratory Diseases

Arachidonate 5-lipoxygenase (ALOX5) plays a central role in allergic and respiratory diseases through its catalysis of arachidonic acid into leukotrienes, potent lipid mediators that drive airway inflammation. In asthma, cysteinyl leukotrienes (LTC4, LTD4, LTE4) generated via the ALOX5 pathway induce bronchoconstriction by contracting airway smooth muscle with potency 1,000 times greater than histamine and a duration up to 30 times longer, contributing significantly to airflow obstruction during exacerbations. These leukotrienes also promote mucus hypersecretion by stimulating goblet cell metaplasia and mucin production in the airway epithelium, exacerbating mucus plugging and impairing mucociliary clearance in asthmatic patients. Clinical evidence supports this involvement, as inhibition of ALOX5 with selective inhibitors like A-64077 reduces cold, dry air-induced bronchoconstriction by 47% in asthmatics, correlating with an 81% decrease in leukotriene B4 (LTB4) synthesis. In bronchoalveolar lavage (BAL) fluid from asthmatics, LTB4 levels are markedly elevated compared to healthy controls, with symptomatic atopic asthmatics showing concentrations of 0.58 ± 0.06 pmol/mL versus 0.36 ± 0.05 pmol/mL in non-atopic controls (p < 0.05), indicating ALOX5-derived LTB4 contributes to ongoing airway inflammation and neutrophil recruitment. Similarly, in allergic rhinitis, cysteinyl leukotrienes mediate eosinophil recruitment by acting as chemotactic factors through the CysLT1 receptor, enhancing eosinophil transendothelial migration and Mac-1 integrin expression, which facilitates their infiltration into nasal mucosa during allergen challenge. This process is evidenced by in vitro studies where LTD4 induces dose-dependent eosinophil chemotaxis and degranulation, and in vivo models where CysLT1 receptor antagonists reduce eosinophil influx in the nasal airways of sensitized animals and humans. Preclinical models have consistently demonstrated ALOX5's mechanistic links to allergic inflammation, with stable findings from studies predating 2020 underscoring its therapeutic relevance. In allergen-sensitized guinea pigs, sheep, and cynomolgus monkeys, ALOX5 inhibition attenuates acute and late-phase bronchoconstriction by up to 80%, reduces neutrophil and eosinophil infiltration in BAL fluid by 58-63%, and normalizes airway hyperresponsiveness to challenges like methacholine. These effects highlight ALOX5's conserved role across species in leukotriene-mediated allergic responses, with no major shifts in understanding reported since early 2000s investigations. Genetic variations, such as promoter polymorphisms in ALOX5, have been briefly associated with increased asthma severity and enhanced LTC4 production by eosinophils in affected individuals.

Cardiovascular Diseases

Arachidonate 5-lipoxygenase (ALOX5) contributes to cardiovascular diseases primarily through its role in generating leukotriene B4 (LTB4), which promotes monocyte adhesion to vascular endothelium and their transformation into foam cells, key steps in atherosclerotic plaque formation. LTB4 acts via its receptor BLT1 to enhance monocyte chemotaxis and adhesion under shear stress conditions, facilitating their recruitment into the arterial wall. Additionally, LTB4 signaling drives lipid uptake and foam cell differentiation in macrophages, exacerbating plaque lipid accumulation and inflammation. This involvement in the inflammatory pathway underscores ALOX5's pro-atherogenic effects in early lesion development. Recent studies highlight ALOX5's role in vascular smooth muscle cell (VSMC) pyroptosis and abdominal aortic aneurysm (AAA) progression. In a 2025 investigation using an angiotensin II-induced AAA model in ApoE^{-/-} mice, ALOX5 expression was elevated in aneurysmal tissues, where it activated the NF-κB pathway to induce NLRP3 inflammasome-mediated pyroptosis in VSMCs. Pharmacological inhibition of ALOX5 with AZD4407 reduced aortic dilation, inflammatory cytokine levels (e.g., IL-1β, IL-6), oxidative stress markers (ROS, MDA), and pyroptotic indicators (caspase-1, GSDMD), thereby attenuating AAA severity. Silencing ALOX5 in mouse aortic VSMCs similarly suppressed angiotensin II-triggered pyroptosis and NF-κB activation, confirming its mechanistic contribution to aneurysmal degeneration. ALOX5 exhibits a dual role in cardiac injury and repair following myocardial infarction (MI). It is essential for the biosynthesis of specialized pro-resolving mediators (SPMs), such as lipoxin A4 and maresin 1, which promote inflammation resolution, neutrophil efferocytosis, and scar formation to support cardiac repair. In a 2022 study using Alox5-null mice subjected to permanent coronary ligation, ALOX5 deficiency led to reduced SPM levels in the infarcted left ventricle and spleen, prolonged neutrophil persistence, elevated proinflammatory eicosanoids (e.g., PGE2), increased myocardium rupture (65% vs. 28% in wild-type), and impaired survival (31% vs. 56%), highlighting its protective function in post-MI healing. Conversely, cardiomyocyte-specific Alox5 overexpression via AAV9 transduction worsens pathological remodeling in pressure overload models, such as transverse aortic constriction, by enhancing Runx2 phase separation, EGFR signaling, fibrosis (increased collagen I, α-SMA), hypertrophy, and left ventricular dysfunction, as evidenced by reduced ejection fraction and enlarged ventricular dimensions. Transgenic models provide evidence of ALOX5's impact on atherosclerosis. In ApoE^{-/-} mice, Alox5 deficiency has been shown to ameliorate atherosclerotic lesion development, particularly under high-fat diet conditions, by limiting leukotriene-mediated inflammation and macrophage accumulation in plaques, despite unchanged plasma lipids. This protective effect aligns with observations in LDLR^{-/-} mice, where partial Alox5 reduction decreased aortic lesion area by over 26-fold, with 5-LO expression localized to macrophage-rich regions.

Cancer

Arachidonate 5-lipoxygenase (ALOX5), also known as 5-LO, plays a significant role in tumor progression by modulating immune evasion and inflammatory signaling within the tumor microenvironment. In glioma, ALOX5 is upregulated, leading to increased production of its metabolite 5-hydroxyeicosatetraenoic acid (5-HETE), which promotes the expression of programmed death-ligand 1 (PD-L1) on glioma-associated microglia/macrophages. This enhancement facilitates immunosuppressive M2 polarization and migration of these cells, thereby enabling tumor immune evasion and supporting glioma progression. High ALOX5 expression serves as a prognostic biomarker across multiple cancers, correlating with poor overall survival and elevated immune cell infiltration in the tumor microenvironment. Pan-cancer analyses indicate that elevated ALOX5 levels are associated with adverse outcomes, including reduced patient survival and increased tumor-infiltrating immune cells, such as macrophages and T cells, which can paradoxically promote an immunosuppressive environment. In specific contexts like low-grade glioma, high ALOX5 expression independently predicts unfavorable prognosis and is linked to heightened immune infiltration scores. In leukemia, ALOX5 expression is dysregulated by genetic alterations, contributing to leukemogenic processes. The MLL-AF4 fusion protein, characteristic of t(4;11) acute lymphoblastic leukemia, directly binds to the ALOX5 promoter via its CXXC domain and activates transcription through redundant domains like AF9ID, pSER, and CHD, thereby upregulating ALOX5 and supporting leukemia cell survival. Similarly, in acute myeloid leukemia (AML), depletion of BRD9 leads to ALOX5 upregulation through chromatin remodeling, particularly in SF3B1-mutated cases, where inverse correlation between BRD9 and ALOX5 expression exacerbates disease progression. Pro-tumorigenic effects of ALOX5 are mediated in part by leukotriene B4 (LTB4) signaling, a downstream product that drives angiogenesis and metastasis. LTB4 promotes vascular endothelial growth factor expression and endothelial cell proliferation, facilitating tumor neovascularization essential for growth and dissemination. In metastatic contexts, such as breast cancer, neutrophil-derived LTB4 enhances cancer cell extravasation and colonization at distant sites, underscoring ALOX5's role in linking inflammation to oncogenic spread. This pathway's activation in tumors often amplifies chronic inflammatory signals that sustain malignancy.

Neurodegenerative and Other Diseases

Arachidonate 5-lipoxygenase (ALOX5) has been implicated in the pathogenesis of tauopathies, where its genetic absence mitigates tau-related pathologies. In mouse models of Alzheimer's disease exposed to homocysteine, which exacerbates tau hyperphosphorylation and synaptic dysfunction, Alox5 knockout prevents memory impairment, reduces tau phosphorylation at disease-relevant sites such as Ser396/Ser404, and preserves synaptic integrity by attenuating oxidative stress and neuroinflammation. This protective effect highlights ALOX5's role in stress-induced tau aggregation and neurodegeneration, suggesting that leukotriene-mediated pathways contribute to synaptic loss in tau-driven disorders. Emerging evidence links ALOX5-derived leukotriene B4 (LTB4) to microglial activation in Alzheimer's disease and potentially Parkinson's disease, driving neuroinflammatory cascades that exacerbate neuronal damage. In Alzheimer's models, LTB4 promotes microglial proliferation and pro-inflammatory cytokine release, amplifying amyloid-beta and tau pathologies through sustained activation of glial cells. Similarly, dysregulation of the leukotriene pathway, including LTB4 signaling, has been observed in Parkinson's disease, where it may enhance microglial responses to alpha-synuclein aggregates, though direct causal links remain under investigation. These findings position ALOX5 inhibition as a potential therapeutic strategy for modulating glial-mediated inflammation in these neurodegenerative conditions. Beyond neurodegeneration, ALOX5 plays a role in liver regeneration, where its upregulation facilitates early hepatocyte proliferation. Following partial hepatectomy in animal models, 5-LOX expression and LTB4 levels increase rapidly, promoting macrophage recruitment and signaling that supports compensatory liver growth; pharmacological inhibition of 5-LOX or LTB4 delays this proliferative response, underscoring their necessity for timely tissue repair. Indirect evidence also connects ALOX5 to polycystic ovary syndrome (PCOS) through inflammation and ferroptosis pathways. In PCOS rat models, the 5-LOX inhibitor zileuton reduces ovarian inflammation, lipid peroxidation, and ferroptotic cell death in granulosa cells, alleviating cyst formation and hormonal imbalances when combined with other agents like silver nanoparticles. This suggests that ALOX5-driven leukotriene production may contribute to oxidative stress and follicular dysfunction in PCOS, warranting further exploration of targeted inhibition.

Pharmacology and Therapeutics

Inhibitors and Modulators

Zileuton is a direct inhibitor of arachidonate 5-lipoxygenase (5-LOX), acting by binding to the enzyme's active site and preventing the oxygenation of arachidonic acid to form 5-hydroperoxyeicosatetraenoic acid (5-HPETE), thereby blocking downstream leukotriene synthesis. Its potency is evidenced by an IC50 value of approximately 0.4 μM in human polymorphonuclear leukocytes (PMNL) for LTB4 biosynthesis inhibition. Indirect modulators of 5-LOX activity primarily target accessory proteins or downstream effectors in the leukotriene pathway. FLAP antagonists, such as MK-886, bind to the 5-lipoxygenase-activating protein (FLAP), disrupting the translocation of 5-LOX to the nuclear membrane and inhibiting the presentation of substrate to the enzyme. This prevents biosynthesis without directly interacting with 5-LOX. receptor blockers like act downstream by antagonizing cysteinyl receptors (CysLT1), thereby modulating the inflammatory effects of 5-LOX-derived leukotrienes such as LTC4, LTD4, and LTE4. Natural inhibitors of 5-LOX include polyphenols and , which interfere with enzyme activation and product formation. , a abundant in fruits and , inhibits 5-LOX by reducing the iron from Fe3+ to Fe2+ and chelating the , thus disrupting the catalytic redox cycle and suppressing production in cellular models. Other , such as those from cocoa, exhibit similar inhibitory effects on recombinant human 5-LOX, with quercetin showing IC50 values in the low micromolar range, and may also prevent enzyme translocation to the perinuclear region via interference with signaling pathways like ERK1/2 and p38 MAPK. Recent developments in 5-LOX inhibition have focused on novel small molecules identified through and structural optimization, targeting 5-HETE production as a key intermediate in leukotriene and proinflammatory mediator synthesis. For instance, long-chain metabolites derived from , such as α-13'-hydroxychromanol, potently inhibit 5-LOX with IC50 values below 1 μM in cell-free and intact cell assays, effectively reducing 5-HETE formation. Substituted 1,2,4-triazoles have emerged as selective FLAP inhibitors that indirectly block 5-LOX-mediated 5-HETE and production, demonstrating high potency in preclinical models. derivatives represent another class of direct 5-LOX inhibitors with IC50 values in the nanomolar range, offering improved selectivity over earlier compounds like zileuton. These advancements, spanning 2020–2025, emphasize structure-based to enhance and specificity for therapeutic applications.

Clinical Applications

Zileuton, a selective inhibitor of arachidonate 5-lipoxygenase (ALOX5), received FDA approval in 1996 for the prophylaxis and chronic treatment of in adults and children aged 12 years and older. Clinical trials have demonstrated that zileuton improves lung function, reduces symptoms, and decreases the frequency of exacerbations compared to , with significant increases in forced expiratory volume in one second (FEV1) observed in patients with mild to moderate . Despite its efficacy, zileuton is associated with potential , including elevated (ALT) levels in up to 1.8% of patients and rare cases of severe , necessitating regular monitoring of . In combination therapies, zileuton added to low-dose inhaled corticosteroids (ICS), such as beclomethasone, has shown benefits in controlling allergic symptoms, offering an alternative to dose escalation of ICS alone by improving pulmonary function and reducing the need for higher doses. In patients with NSAID-exacerbated respiratory disease (), also known as (), zileuton mitigates symptoms by blocking the shunting of metabolism toward the pathway, which is hyperactive in this condition. Clinical evidence indicates that zileuton reduces the frequency and severity of respiratory exacerbations in , improves sinonasal , and may decrease reliance on systemic corticosteroids, particularly when combined with standard management. As of November 2025, emerging clinical applications include investigations of zileuton in early-phase trials for preventing severe reactions in food allergies, based on preclinical evidence of blocking leukotriene-mediated . Additionally, the FLAP inhibitor atuliflapon is in phase 2/3 clinical trials for moderate-to-severe .

Genetic Variations

Polymorphisms and Mutations

The promoter region of the ALOX5 gene contains a (VNTR) polymorphism consisting of Sp1/Egr-1 binding motifs (GGGCGG), with the most common featuring five repeats and variants ranging from three to nine repeats ( denoted as 3, 4, 5, 6, 7, 8, or 9). This polymorphism modulates ALOX5 transcription by altering the number of Sp1 binding sites, with shorter (e.g., 3 or 4 repeats) generally associated with reduced promoter activity compared to the wild-type five-repeat . Longer (e.g., 6 or more repeats) have been observed at lower frequencies in certain populations and may enhance transcriptional efficiency under specific regulatory contexts. Missense mutations in ALOX5 are rare and typically identified through targeted sequencing or analysis, often resulting in altered activity. For instance, the variant p.Glu254Lys (rs2228065) substitutes with at position 254, potentially disrupting the protein's catalytic domain without significant accumulation in pathways in studied cohorts. Another example is p.Pro224Leu (rs2241002), a polymorphism that has been cataloged in variant databases but shows limited evidence of widespread functional impairment. More recent deep resequencing has uncovered additional rare missense variants, such as those leading to substitutions like Arg to Gln, which do not exhibit statistically significant differences in production but may subtly affect . The ALOX5AP gene, encoding the 5-lipoxygenase-activating protein (FLAP), harbors several polymorphisms, including multi-single nucleotide polymorphism (SNP) haplotypes that influence leukotriene biosynthesis. The HapB haplotype, defined by the combination rs17216473A–rs10507391A–rs9315050A–rs17222842G, represents a common variant block associated with modulated FLAP function. Variants in related regulators, such as those in the SGK1 gene (serum/glucocorticoid-regulated kinase 1), have been noted in genomic studies for their potential indirect effects on the ALOX5 pathway through ion channel regulation, though direct linkage to FLAP remains under investigation. Other ALOX5AP SNPs, like rs17222842, contribute to haplotype diversity without dominant loss-of-function effects. Exome sequencing efforts post-2020 have revealed rare deleterious in ALOX5, expanding the catalog of coding variants. A notable example is the c.1700A>G (p.Asn567Ser) identified in a patient with osteomesopyknosis via , located in 13 within a conserved low-complexity region; this variant promotes protein misfolding and proteasomal degradation, leading to reduced ALOX5 protein levels. Burden analyses in larger cohorts, including those with or inflammatory conditions, have detected additional low-frequency and protein-truncating in ALOX5 and ALOX5AP, though their aggregate impact on pathway activity requires further validation. These findings from databases like gnomAD highlight the rarity of such , with minor frequencies often below 0.01%.

Associations with Diseases

Genetic variants in the ALOX5 gene, particularly in the Sp1-binding promoter region consisting of variable tandem repeats, have been associated with increased risk and severity of allergic asthma. Individuals carrying non-5/5 genotypes (e.g., 4/5 or 6/5) exhibit higher production of leukotriene C4 by eosinophils and are more likely to experience moderate-to-severe asthma phenotypes compared to those with the wild-type 5/5 genotype, with odds ratios for severe disease ranging from 1.5 to 2.0 in pediatric cohorts. Meta-analyses of multiple studies confirm that these promoter variants contribute to airway hyperresponsiveness and poorer asthma control, though associations with overall susceptibility are inconsistent across populations. Additionally, the minor allele of the Sp1 tandem repeat polymorphism is linked to increased leukotriene production and reduced lung function in children with poorly controlled asthma, supporting a role in exacerbating inflammatory responses. In cardiovascular diseases, haplotypes in the ALOX5AP gene, which encodes the 5-lipoxygenase-activating protein essential for ALOX5 function, show strong associations with and risk. The , comprising specific single nucleotide polymorphisms such as rs17216473 and rs10507391, increases the odds of MI by approximately 20-30% in meta-analyses of European and Asian populations, with similar effects observed for atherothrombotic (odds ratio ~1.2-1.4). A comprehensive Epidemiology (HuGE) review and further substantiates the HapB linkage to susceptibility, highlighting its role in leukotriene-mediated vascular inflammation, though replication in diverse cohorts remains variable. These findings underscore ALOX5AP variants as contributors to progression, independent of traditional risk factors like . Transgenic and human studies further elucidate these links through Alox5-deficient models. In Alox5^{-/-} knockout mice crossed with LDL receptor-null backgrounds, lesion formation in models is significantly reduced by 40-50%, attributed to diminished B4-mediated recruitment and vascular . Similarly, Alox5^{-/-} mice display attenuated airway and hyperresponsiveness in ovalbumin-induced models, with reduced Th2 production and hypersecretion mirroring protective effects observed in human carriers of low-activity ALOX5 promoter variants. Variant knock-in studies in humans confirm that low-expression alleles correlate with decreased inflammatory markers in and patients, supporting therapeutic targeting of the pathway.

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