Arachidonate 5-lipoxygenase
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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
The ALOX5 gene, which occupies 71.9 kilo
Expression
Cells primarily involved in regulating
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
Studies with cultured human cells have found that there are a large number of ALOX5
Biochemistry
Human ALOX5 is a soluble, monomeric
- A C-terminalcatalytic domain (residues 126–673)
- An COL1), and Dicerprotein
- 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 tyrosine kinase receptors.
The enzyme possesses two catalytic activities as illustrated by its metabolism of
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
ALOX5 exists primarily in the cytoplasm and nucleoplasm of cells. Upon cell stimulation, ALOX5: a) may be phosphorylated on
In addition to its activation, ALOX5 must gain access to its
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
Substrates, metabolites, and metabolite activities
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
ALOX5 metabolizes the
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
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
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
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
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
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
Inflammation
Studies implicate ALOX5 in contributing to
- acute pathogen invasion, trauma, and burns (see Inflammation § Causes)
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
Allergy
ALOX5 contributes to the development and progression of allergy and allergic inflammation reactions and diseases such as:
- allergic rhinitis
- conjunctivitis
- asthma
- rashes
- eczema (see Allergy § Signs and symptoms).
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
ALOX5 contributes to non-allergic NSAID hypersensitivity reactions of the respiratory system and skin such as:
- aspirin-exacerbated respiratory disease
- nonallergic rhinitis
- non-allergic conjunctivitis
- angioedema
- urticarial.
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
The tissue, animal model, and animal and human genetic studies cited above implicate ALOX5 in a wide range of diseases:
- excessive inflammatory responses to pathogens, trauma, burns, and other forms of tissue injury (see Inflammation § Causes)
- chronic inflammatory conditions such as:
(see Inflammation § Disorders)
- allergy and allergic inflammation reactions such as:
- allergic rhinitis
- conjunctivitis
- asthma
- rashes
- eczema
- NSAID-induced acute non-allergic reactions such as:
- asthma
- rhinitis
- conjunctivitis
- angioedema
- urticaria
- the progression of certain cancers such as those of the prostate and pancreas.
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. 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,
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
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
The upstream
NSAID-induced non-allergic reactions
Atherosclerosis
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
Arachidonate 5-lipoxygenase inhibitor
References
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Further reading
- Rådmark OP (2000). "The molecular biology and regulation of 5-lipoxygenase". Am. J. Respir. Crit. Care Med. 161 (2 Pt 2): S11–5. PMID 10673219.
- Hammarberg T, Reddy KV, Persson B, Rådmark O (2002). "Calcium Binding to 5-Lipoxygenase". In Honn KV, Marnett LJ, Nigam S, Dennis E, Serhan C (eds.). Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation, and Radiation Injury, 5. Advances in Experimental Medicine and Biology. Vol. 507. Springer. pp. 117–121. PMID 12664574.
- Ishii S, Noguchi M, Miyano M, Matsumoto T, Noma M (1992). "Mutagenesis studies on the amino acid residues involved in the iron-binding and the activity of human 5-lipoxygenase". Biochem. Biophys. Res. Commun. 182 (3): 1482–1490. PMID 1540191.
- Nguyen T, Falgueyret JP, Abramovitz M, Riendeau D (1991). "Evaluation of the role of conserved His and Met residues among lipoxygenases by site-directed mutagenesis of recombinant human 5-lipoxygenase". J. Biol. Chem. 266 (32): 22057–22062. PMID 1939225.
- Hoshiko S, Rådmark O, Samuelsson B (1990). "Characterization of the human 5-lipoxygenase gene promoter". Proc. Natl. Acad. Sci. U.S.A. 87 (23): 9073–9077. PMID 2251250.
- Matsumoto T, Funk CD, Rådmark O, Höög JO, Jörnvall H, Samuelsson B (1988). "Molecular cloning and amino acid sequence of human 5-lipoxygenase". Proc. Natl. Acad. Sci. U.S.A. 85 (1): 26–30. PMID 2829172.
- Rouzer CA, Kargman S (1988). "Translocation of 5-lipoxygenase to the membrane in human leukocytes challenged with ionophore A23187". J. Biol. Chem. 263 (22): 10980–10988. PMID 3134355.
- Dixon RA, Jones RE, Diehl RE, Bennett CD, Kargman S, Rouzer CA (1988). "Cloning of the cDNA for human 5-lipoxygenase". Proc. Natl. Acad. Sci. U.S.A. 85 (2): 416–420. PMID 3422434.
- Jakobsson PJ, Shaskin P, Larsson P, Feltenmark S, Odlander B, Aguilar-Santelises M, Jondal M, Biberfeld P, Claesson HE (1995). "Studies on the regulation and localization of 5-lipoxygenase in human B-lymphocytes". Eur. J. Biochem. 232 (1): 37–46. PMID 7556168.
- Janssen-Timmen U, Vickers PJ, Wittig U, Lehmann WD, Stark HJ, Fusenig NE, Rosenbach T, Rådmark O, Samuelsson B, Habenicht AJ (1995). "Expression of 5-lipoxygenase in differentiating human skin keratinocytes". Proc. Natl. Acad. Sci. U.S.A. 92 (15): 6966–6970. PMID 7624354.
- Lepley RA, Fitzpatrick FA (1994). "5-Lipoxygenase contains a functional Src homology 3-binding motif that interacts with the Src homology 3 domain of Grb2 and cytoskeletal proteins". J. Biol. Chem. 269 (39): 24163–24168. PMID 7929073.
- Shaw KJ, Ng C, Kovacs BW (1994). "Cyclooxygenase gene expression in human endometrium and decidua". Prostaglandins Leukot. Essent. Fatty Acids. 50 (5): 239–243. PMID 8066098.
- Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174. PMID 8125298.
- Woods JW, Evans JF, Ethier D, Scott S, Vickers PJ, Hearn L, Heibein JA, Charleson S, Singer II (1993). "5-lipoxygenase and 5-lipoxygenase-activating protein are localized in the nuclear envelope of activated human leukocytes". J. Exp. Med. 178 (6): 1935–1946. PMID 8245774.
- Mancini JA, Li C, Vickers PJ (1993). "5-Lipoxygenase activity in the human pancreas". J Lipid Mediat. 8 (3): 145–150. PMID 8268460.
- VanderNoot VA, Fitzpatrick FA (1995). "Competitive binding assay of src homology domain 3 interactions between 5-lipoxygenase and growth factor receptor binding protein 2". Anal. Biochem. 230 (1): 108–114. PMID 8585605.
- Brock TG, McNish RW, Bailie MB, Peters-Golden M (1997). "Rapid import of cytosolic 5-lipoxygenase into the nucleus of neutrophils after in vivo recruitment and in vitro adherence". J. Biol. Chem. 272 (13): 8276–8280. PMID 9079648.
- Nassar GM, Montero A, Fukunaga M, Badr KF (1997). "Contrasting effects of proinflammatory and T-helper lymphocyte subset-2 cytokines on the 5-lipoxygenase pathway in monocytes". Kidney Int. 51 (5): 1520–1528. PMID 9150468.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156. PMID 9373149.
External links
- Arachidonate+5-Lipoxygenase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Human ALOX5 genome location and ALOX5 gene details page in the UCSC Genome Browser.