View source for Arachidonate 5-lipoxygenase

{{Short description|Class of enzymes}}
{{Infobox gene}}
{{infobox enzyme
| Name       = arachidonate 5-lipoxygenase
| EC_number  = 1.13.11.34
| CAS_number = 80619-02-9{{dead link|fix-attempted=yes|date=September 2023}}
| GO_code    = 0004051
| image      =
| width      =
| caption    =
}}
'''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]].<ref name="pmid2565035">{{cite journal | vauthors = Funk CD, Hoshiko S, Matsumoto T, Rdmark O, Samuelsson B | title = Characterization of the human 5-lipoxygenase gene | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 8 | pages = 2587–2591 | date = Apr 1989 | pmid = 2565035 | pmc = 286962 | doi = 10.1073/pnas.86.8.2587 | bibcode = 1989PNAS...86.2587F | doi-access = free }}</ref> Arachidonate 5-lipoxygenase is a member of the [[lipoxygenase]] family of enzymes. It transforms essential fatty acids ([[Essential fatty acid|EFA]]) substrates into [[leukotriene]]s 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[[base pair]]s (kb) on chromosome 10 (all other human lipoxygenases are clustered together on chromosome 17), is composed of 14 [[exon]]s divided by 13 [[intron]]s encoding the mature 78 [[kilodalton]] (kDa) ALOX5 protein consisting of 673 amino acids. The [[gene promoter]] region of ALOX5 contains 8 [[GC box]]es but lacks [[TATA box]]es or [[CAT box]]es and thus resembles the gene promoters of typical [[housekeeping gene]]s. Five of the 8 GC boxes are arranged in tandem and are recognized by the transcription factors [[Transcription factor Sp1|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.<ref name="pmid24020397">{{cite journal | vauthors = Ochs MJ, Suess B, Steinhilber D | title = 5-lipoxygenase mRNA and protein isoforms | journal = Basic & Clinical Pharmacology & Toxicology | volume = 114 | issue = 1 | pages = 78–82 | year = 2014 | pmid = 24020397 | doi = 10.1111/bcpt.12115 | doi-access = free }}</ref>
== Expression ==
Cells primarily involved in regulating [[inflammation]], [[allergy]], and other [[immune response]]s, e.g. [[neutrophil]]s, [[eosinophil]]s, [[basophil]]s, [[monocyte]]s, [[macrophage]]s, [[mast cell]]s, [[dendritic cell]]s, and [[B-lymphocyte]]s express ALOX5. [[Platelet]]s, [[T cell]]s, and [[erythrocyte]]s are ALOX5-negative. In skin, [[Langerhans cell]]s strongly express ALOX5. [[Fibroblast]]s, [[smooth muscle]] cells and [[endothelial cell]]s express low levels of ALOX5.<ref name="pmid24020397" /><ref name="pmid24313690">{{cite journal | vauthors = Anwar Y, Sabir JS, Qureshi MI, Saini KS | title = 5-lipoxygenase: a promising drug target against inflammatory diseases-biochemical and pharmacological regulation | journal = Current Drug Targets | volume = 15 | issue = 4 | pages = 410–422 | year = 2014 | pmid = 24313690 | doi = 10.2174/1389450114666131209110745}}</ref> Up-regulation of ALOX5 may occur during the maturation of [[leukocyte]]s 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.<ref name="pmid24020397" />
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&nbsp;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.<ref name="pmid24020397" />
== Biochemistry ==
Human ALOX5 is a soluble, monomeric [[protein]] consisting of 673 [[amino acid]]s with a [[molecular weight]] of ~78 [[kDa]]. Structurally, ALOX5 possesses:<ref name="pmid24313690" /><ref name="Rådmark_2015">{{cite journal | vauthors = Rådmark O, Werz O, Steinhilber D, Samuelsson B | title = 5-Lipoxygenase, a key enzyme for leukotriene biosynthesis in health and disease | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | volume = 1851 | issue = 4 | pages = 331–339 | year = 2015 | pmid = 25152163 | doi = 10.1016/j.bbalip.2014.08.012 }}</ref>
* A [[C-terminal]] catalytic domain (residues 126–673)
* An [[N-terminal]] [[C2-like domain]] which promotes its binding to ligand substrates, Ca<sup>2+</sup>, 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 domain]]s 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. HO<sub>2</sub>) residue to arachidonic acid (i.e. 5''Z'',8''Z'',11''Z'',14''Z''-eicosatetraenoic acid) at carbon 5 of its 1,4 diene group (i.e. its 5''Z'',8''Z'' double bonds) to form 5(''S'')-hydroperoxy-6''E'',8''Z'',11''Z'',14''Z''-eicosatetraenoic acid (i.e. 5''S''-HpETE).<ref>Reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R01595 R01595] at KEGG Pathway Database.</ref> The 5''S''-HpETE intermediate may then be released by the enzyme and rapidly reduced by cellular [[glutathione peroxidase]]s to its corresponding alcohol, 5(''S'')-hydroxy-6''E'',8''Z'',11''Z'',14''Z''-eicosatetraenoic acid (i.e. [[5-HETE]]), or, alternatively, further metabolized by ALOX5's epoxidase (also termed LTA4 synthase) activity which converts 5''S''-HpETE to its [[epoxide]], 5''S'',6''S''-hydroxy-6''E'',8''Z'',11''Z'',14''Z''-eicosatetraenoic acid (i.e. [[LTA4]]).<ref>Reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R03058 R03058] at KEGG Pathway Database.</ref>  LTA4 is then acted on by a separate, soluble enzyme, [[leukotriene-A4 hydrolase]], to form the dihydroxyl product, [[leukotriene B4]] (LTB4, i.e. 5''S'',12''R''-dihydroxy-5''S'',6''Z'',8''E'',10''E'',12''R'',14''Z''-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. 5''S''-hydroxy,6''R''-(S-glutathionyl)-7''E'',9''E'',11''Z'',14''Z''-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]].<ref name="Rådmark_2015" /><ref name="pmid26066610">{{cite journal | vauthors = Ahmad S, Thulasingam M, Palombo I, Daley DO, Johnson KA, Morgenstern R, Haeggström JZ, Rinaldo-Matthis A | title = Trimeric microsomal glutathione transferase 2 displays one third of the sites reactivity | journal = Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics | volume = 1854 | issue = 10 Pt A | pages = 1365–1371 | year = 2015 | pmid = 26066610 | doi = 10.1016/j.bbapap.2015.06.003 }}</ref> 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 {{slink|Lipoxygenase|Mouse lipoxygenases}}).
== Regulation ==
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 kinase]]s, [[S6 kinase]], [[protein kinase A]] (PKA), [[protein kinase C]], [[Cdc2]], and/or a Ca<sup>2+</sup>/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 Ca<sup>2+</sup> 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 [[Chemotaxis|chemotactic factor]]s on leukocytes. Rises in cytosolic Ca<sup>2+</sup>, ALOX5's movement to membranes, and ALOX5's interaction with FLAP are critical to the physiological activation of the enzyme.<ref name="pmid24313690" />  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.<ref name="Rådmark_2015" /><ref name="Haeggström_2011">{{cite journal | vauthors = Haeggström JZ, Funk CD | title = Lipoxygenase and leukotriene pathways: biochemistry, biology, and roles in disease | journal = Chemical Reviews | volume = 111 | issue = 10 | pages = 5866–5898 | year = 2011 | pmid = 21936577 | doi = 10.1021/cr200246d | url = https://zenodo.org/record/3424215 }}{{Dead link|date=April 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>
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 ''[[Glycerophospholipid#Nomenclature and stereochemistry|sn]]''2 position of membrane [[phospholipid]]s, in order to form biologically active products. This is accomplished by a large family of [[phospholipase A2]] (PLA<sub>2</sub>) enzymes. The cytosolic PLA<sub>2</sub> set (i.e. cPLA<sub>2</sub>s) of PLA<sub>2</sub> enzymes (see {{slink|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 Ca<sup>2+</sup> which triggers cPLA<sub>2</sub>s, particularly the α isoform (cPLA<sub>2</sub>α), to move from its normal residence in the cytosol to cellular membranes. This chemotactic factor stimulation concurrently causes the activation of [[mitogen-activated protein kinase]]s (MAPK) which in turn stimulates the activity of cPLA<sub>2</sub>α by phosphorylating it on ser-505 (other cell types may activate this or other cPLA<sub>2</sub> isoforms using other kinases which phosphorylate them on different serine residues). These two events allow cPLA<sub>2</sub>s to release PUFA esterified to membrane phospholipids to FLAP which then presents them to ALOX5 for their metabolism.<ref name="pmid9131168">{{cite book | vauthors = Wykle RL, Wijkander J, Nixon AB, Daniel LW, O'Flaherty JT | title = Platelet-Activating Factor and Related Lipid Mediators 2 | chapter = Activation of 85 kDa PLA2 by Eicosanoids in Human Neutrophils and Eosinophils | series = Advances in Experimental Medicine and Biology | volume = 416 | pages = 327–331 | year = 1996 | pmid = 9131168 | doi = 10.1007/978-1-4899-0179-8_52 | isbn = 978-1-4899-0181-1 }}</ref><ref name="pmid18931897">{{cite journal | vauthors = Burke JE, Dennis EA | title = Phospholipase A2 biochemistry | journal = Cardiovascular Drugs and Therapy | volume = 23 | issue = 1 | pages = 49–59 | year = 2009 | pmid = 18931897 | pmc = 2823292 | doi = 10.1007/s10557-008-6132-9 }}</ref>
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 Ca<sup>2+</sup>, this binding also alters the relative levels of hydroperoxy versus epoxide (see arachidonic acid section below) products made by ALOX5.<ref name="pmid24313690" /><ref name="Rådmark_2015" /> 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.<ref name="Rådmark_2015" /> The presence of certain [[diacylglycerol]]s such as 1-oleoyl-2-acetyl-''sn''-glycerol, 1-hexadecyl-2-acetyl-''[[Glycerophospholipid#Nomenclature and stereochemistry|sn]]''-glycerol, and 1-''O''-hexadecyl-2-acetyl-<abbr title="stereospecifically numbered glycerol">''sn''-glycerol</abbr>, and 1,2-dioctanoyl-''sn''-glycerol but not 1-stearoyl-2-arachidonyl-''sn''-glycerol increase the catalytic activity of ALOX5 in vitro.<ref name="Rådmark_2015" />
== 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.
[[File:ALOX5_REACTION.png|880px]]
=== Arachidonic acid ===
ALOX5 metabolizes the [[omega-6 fatty acid]], [[arachidonic acid]] (AA, i.e. 5''Z'',8''Z'',11''Z'',14''Z''-eicosatetraenoic acid), to 5-hydroperoxyeicosatetraenoic acid ([[5-hydroperoxyeicosatetraenoic acid|5-HpETE]]) which is then rapidly converted to physiologically and pathologically important products. Ubiquitous cellular [[glutathione peroxidase]]s (GPXs) reduce 5-HpETE to 5-hydroxyeicosatetraenoic acid ([[5-Hydroxyeicosatetraenoic acid|5-HETE]]); 5-HETE may be further metabolized by [[5-Hydroxyeicosanoid dehydrogenase|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 [[ABCC1|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 {{slink|Specialized pro-resolving mediators|Lipoxins}}).<ref name="pmid24313690" /><ref name="pmid25895638">{{cite journal | vauthors = Romano M, Cianci E, Simiele F, Recchiuti A | title = Lipoxins and aspirin-triggered lipoxins in resolution of inflammation | journal = European Journal of Pharmacology | volume = 760 | pages = 49–63 | year = 2015 | pmid = 25895638 | doi = 10.1016/j.ejphar.2015.03.083 }}</ref><ref name="pmid25449650">{{cite journal | vauthors = Powell WS, Rokach J | title = Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | volume = 1851 | issue = 4 | pages = 340–355 | year = 2015 | pmid = 25449650 | doi = 10.1016/j.bbalip.2014.10.008 | pmc = 5710736 }}</ref><ref name="pmid25572555">{{cite journal | vauthors = Liu M, Yokomizo T | title = The role of leukotrienes in allergic diseases | journal = Allergology International | volume = 64 | issue = 1 | pages = 17–26 | year = 2015 | pmid = 25572555 | doi = 10.1016/j.alit.2014.09.001 | doi-access = free }}</ref> GPXs, 5-HEDH, LTA4H, LTC4S, ABCC1, and cell surface peptidases may act similarly on the ALOX5-derived metabolites of other PUFA.
[[LTB4]], [[5-Hydroxyeicosatetraenoic acid|5-HETE]], and [[5-Oxo-eicosatetraenoic acid|5-oxo-ETE]] may contribute to the [[innate immune response]] as leukocyte [[Chemotaxis|chemotactic factor]]s, 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 response]]s (5-HETE and LTB4). 5-Oxo-ETE is a particularly potent chemotactic factor for and activator of [[eosinophil]]s and may thereby contribute to eosinophil-based allergic reactions and diseases.<ref name="Rådmark_2015" /><ref name="pmid24056189">{{cite journal | vauthors = Powell WS, Rokach J | title = The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor | journal = Progress in Lipid Research | volume = 52 | issue = 4 | pages = 651–665 | year = 2013 | pmid = 24056189 | doi = 10.1016/j.plipres.2013.09.001 | pmc=5710732}}</ref> 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]].<ref name="pmid24056189" /><ref name="Biochim. Biophys 2005">{{cite journal | vauthors = O'Flaherty JT, Rogers LC, Paumi CM, Hantgan RR, Thomas LR, Clay CE, High K, Chen YQ, Willingham MC, Smitherman PK, Kute TE, Rao A, Cramer SD, Morrow CS | title = 5-Oxo-ETE analogs and the proliferation of cancer cells | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | volume = 1736 | issue = 3 | pages = 228–236 | date = October 2005 | pmid = 16154383 | doi = 10.1016/j.bbalip.2005.08.009 }}</ref><ref>{{cite journal | vauthors = Avis IM, Jett M, Boyle T, Vos MD, Moody T, Treston AM, Martínez A, Mulshine JL | title = Growth control of lung cancer by interruption of 5-lipoxygenase-mediated growth factor signaling | journal = The Journal of Clinical Investigation | volume = 97 | issue = 3 | pages = 806–813 | date = February 1996 | pmid = 8609238 | pmc = 507119 | doi = 10.1172/JCI118480 }}</ref><ref name="Oncology 65:285-294, 2003">{{cite journal | vauthors = Ding XZ, Tong WG, Adrian TE | title = Multiple signal pathways are involved in the mitogenic effect of 5(S)-HETE in human pancreatic cancer | journal = Oncology | volume = 65 | issue = 4 | pages = 285–294 | date = 2003 | pmid = 14707447 | doi = 10.1159/000074640 | s2cid = 22159108 }}</ref><ref name="pmid26686687">{{cite journal | vauthors = Hu Y, Li S | title = Survival regulation of leukemia stem cells | journal = Cellular and Molecular Life Sciences | volume = 73 | issue = 5 | pages = 1039–1050 | year = 2016 | pmid = 26686687 | doi = 10.1007/s00018-015-2108-7 | s2cid = 2744344 | pmc = 11108378 }}</ref> ALOX5 and its LTB4 metabolite as well as this metabolite's [[Leukotriene B4 receptor 1|BLT1]] and [[BLT2]] receptors have also been shown to promote the growth of various types of human cancer cell lines in culture.<ref name="pmid24588652">{{cite journal | vauthors = Bäck M, Powell WS, Dahlén SE, Drazen JM, Evans JF, Serhan CN, Shimizu T, Yokomizo T, Rovati GE | title = Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7 | journal = British Journal of Pharmacology | volume = 171 | issue = 15 | pages = 3551–3574 | year = 2014 | pmid = 24588652 | pmc = 4128057 | doi = 10.1111/bph.12665 }}</ref><ref name="pmid23977445">{{cite journal | vauthors = Cho NK, Joo YC, Wei JD, Park JI, Kim JH | title = BLT2 is a pro-tumorigenic mediator during cancer progression and a therapeutic target for anti-cancer drug development | journal = American Journal of Cancer Research | volume = 3 | issue = 4 | pages = 347–355 | year = 2013 | pmid = 23977445 | pmc = 3744015 }}</ref>
[[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]].<ref name="pmid24313690" /> 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.<ref name="pmid24588652" />
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]]).<ref name="pmid25895638" />
=== Mead acid ===
[[Mead acid]] (i.e. 5''Z'',8''Z'',11''Z''-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-6''E'',8''Z'',11''Z''-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.<ref name="pmid25449650" /> 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. 4''Z'',8''Z'',11''Z'',14''Z'',17''Z''-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.<ref name="Rådmark_2015" /><ref name="Maaløe_2011">{{cite journal | vauthors = Maaløe T, Schmidt EB, Svensson M, Aardestrup IV, Christensen JH | title = The effect of n-3 polyunsaturated fatty acids on leukotriene B<sub>4</sub> and leukotriene B<sub>5</sub> production from stimulated neutrophil granulocytes in patients with chronic kidney disease | journal = Prostaglandins, Leukotrienes, and Essential Fatty Acids | volume = 85 | issue = 1 | pages = 37–41 | date = Jul 2011 | pmid = 21530211 | doi = 10.1016/j.plefa.2011.04.004 }}</ref> 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 [[resolvin]]s of the E series (see {{slink|Specialized pro-resolving mediators|EPA-derived resolvins}} for further details on this metabolism) viz., resolvin E1 (RvE1) and RvE2.<ref name="pmid25857211">{{cite journal | vauthors = Serhan CN, Chiang N, Dalli J | title = The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution | journal = Seminars in Immunology | volume = 27 | issue = 3 | pages = 200–215 | year = 2015 | pmid = 25857211 | pmc = 4515371 | doi = 10.1016/j.smim.2015.03.004 }}</ref><ref name="pmid25052386">{{cite journal | vauthors = Qu Q, Xuan W, Fan GH | title = Roles of resolvins in the resolution of acute inflammation | journal = Cell Biology International | volume = 39 | issue = 1 | pages = 3–22 | year = 2015 | pmid = 25052386 | doi = 10.1002/cbin.10345 | s2cid = 10160642 }}</ref>
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.<ref name="Rådmark_2015" /><ref name="Maaløe_2011" /> RvE1 and ReV2 are [[specialized pro-resolving mediators]] that contribute to the resolution of inflammation and other reactions.<ref name="pmid25052386" />
=== Docosahexaenoic acid ===
ALOX5 acts in series with [[ALOX15]] to metabolize the omega 3 fatty acid, [[docosahexaenoic acid]] (DHA, i.e. 4''Z'',7''Z'',10''Z'',13''Z'',16''Z'',19''Z''-docosahexaenoic acid), to D series resolvins (see {{slink|Specialized pro-resolving mediators|DHA-derived resolvins}} for further details on this metabolism).<ref name="pmid25052386" /><ref name="pmid26655290">{{cite journal | vauthors = Barden AE, Mas E, Mori TA | title = n-3 Fatty acid supplementation and proresolving mediators of inflammation | journal = Current Opinion in Lipidology | volume = 27 | issue = 1 | pages = 26–32 | year = 2016 | pmid = 26655290 | doi = 10.1097/MOL.0000000000000262 | s2cid = 45820130 | url = https://api.research-repository.uwa.edu.au/files/26432732/N_3_Fatty_acid_supplementation_and_prorresolving_mediators_of_inflammation._AAM_ID_11273143.docx }}</ref>
The D series [[resolvin]]s (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.<ref name="pmid25052386" /><ref name="pmid26655290" />
== 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 [[pathogen]]s. 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]]''.<ref name="Haeggström_2011" /><ref name="pmid23991239">{{cite journal | vauthors = Santos PC, Santos DA, Ribeiro LS, Fagundes CT, de Paula TP, Avila TV, Baltazar Lde M, Madeira MM, Cruz Rde C, Dias AC, Machado FS, Teixeira MM, Cisalpino PS, Souza DG | title = The pivotal role of 5-lipoxygenase-derived LTB4 in controlling pulmonary paracoccidioidomycosis | journal = PLOS Neglected Tropical Diseases | volume = 7 | issue = 8 | pages = e2390 | year = 2013 | pmid = 23991239 | pmc = 3749973 | doi = 10.1371/journal.pntd.0002390 | doi-access = free }}</ref> 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]].<ref>{{cite web | url = https://www.wikigenes.org/e/gene/e/11689.html | title = Alox5 – arachidonate 5-lipoxygenase | work = WikiGenes }}</ref>  On the other hand, ALOX5 gene knockout mice demonstrate an enhanced resistance and lessened pathology to ''[[Brucella abortus]]'' infection<ref name="pmid25583526">{{cite journal | vauthors = Fahel JS, de Souza MB, Gomes MT, Corsetti PP, Carvalho NB, Marinho FA, de Almeida LA, Caliari MV, Machado FS, Oliveira SC | title = 5-Lipoxygenase negatively regulates Th1 response during ''Brucella abortus'' infection in mice | journal = Infection and Immunity | volume = 83 | issue = 3 | pages = 1210–1216 | year = 2015 | pmid = 25583526 | pmc = 4333460 | doi = 10.1128/IAI.02592-14 }}</ref> and, at least in its acute phase, ''[[Trypanosoma cruzi]]'' infection.<ref name="pmid25165415">{{cite journal | vauthors = Canavaci AM, Sorgi CA, Martins VP, Morais FR, de Sousa ÉV, Trindade BC, Cunha FQ, Rossi MA, Aronoff DM, Faccioli LH, Nomizo A | title = The acute phase of ''Trypanosoma cruzi'' infection is attenuated in 5-lipoxygenase-deficient mice | journal = Mediators of Inflammation | volume = 2014 | pages = 893634 | year = 2014 | pmid = 25165415 | pmc = 4137569 | doi = 10.1155/2014/893634 | doi-access = free }}</ref> 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 [[cornea]]l 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.<ref name="pmid25857211" /><ref name="pmid25359497">{{cite journal | vauthors = Serhan CN, Chiang N, Dalli J, Levy BD | title = Lipid mediators in the resolution of inflammation | journal = Cold Spring Harbor Perspectives in Biology | volume = 7 | issue = 2 | pages = a016311 | year = 2015 | pmid = 25359497 | doi = 10.1101/cshperspect.a016311 | pmc=4315926}}</ref>
''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 cell]]s and CD8+ T [[cytotoxic T cell]]s to the sites of implantation.<ref name="pmid26663781">{{cite journal | vauthors = Poczobutt JM, Nguyen TT, Hanson D, Li H, Sippel TR, Weiser-Evans MC, Gijon M, Murphy RC, Nemenoff RA | title = Deletion of 5-Lipoxygenase in the Tumor Microenvironment Promotes Lung Cancer Progression and Metastasis through Regulating T Cell Recruitment | journal = Journal of Immunology | volume = 196 | issue = 2 | pages = 891–901 | year = 2016 | pmid = 26663781 | pmc = 4705594 | doi = 10.4049/jimmunol.1501648 }}</ref> 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 [[innate immunity]] by contributing to the mounting inflammatory responses to a wide range of diseases:
* acute [[pathogen]] invasion, trauma, and burns (see {{slink|Inflammation|Causes}})
however, ALOX5 also contributes to the development and progression of excessive and chronic inflammatory responses such as:
* [[rheumatoid arthritis]]
* [[atherosclerosis]]
* [[inflammatory bowel disease]]
* [[autoimmune disease]]s
(see {{slink|Inflammation|Disorders}}).
These dual functions probably reflect ALOX5's ability to form the: '''a)''' potent chemotactic factor, LTB4, and possibly also weaker chemotactic factor, 5''S''-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.<ref name="Haeggström_2011" /><ref name="pmid1668115">{{cite journal | vauthors = Rossi AG, O'Flaherty JT | title = Bioactions of 5-hydroxyicosatetraenoate and its interaction with platelet-activating factor | journal = Lipids | volume = 26 | issue = 12 | pages = 1184–1188 | year = 1991 | pmid = 1668115 | doi = 10.1007/bf02536528| s2cid = 3964822 }}</ref><ref name="pmid26688348">{{cite journal | vauthors = Basil MC, Levy BD | title = Specialized pro-resolving mediators: endogenous regulators of infection and inflammation | journal = Nature Reviews. Immunology | volume = 16 | issue = 1 | pages = 51–67 | year = 2016 | pmid = 26688348 | doi = 10.1038/nri.2015.4 | pmc = 5242505 }}</ref>
=== Allergy ===
ALOX5 contributes to the development and progression of [[allergy]] and [[allergic inflammation]] reactions and diseases such as:
* allergic [[rhinitis]]
* [[conjunctivitis]]
* [[asthma]]
* [[rash]]es
* [[eczema]] (see {{slink|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]].<ref name="Haeggström_2011" /><ref name="pmid24056189" /> 5-Oxo-ETE and, to a lesser extent, 5''S''-HETE, also act synergistically with another pro-allergic mediator, [[platelet-activating factor]], to stimulate and otherwise activate eosinophils.<ref name="pmid24056189" /><ref name="pmid26678823">{{cite journal | vauthors = Oussalah A, Mayorga C, Blanca M, Barbaud A, Nakonechna A, Cernadas J, Gotua M, Brockow K, Caubet JC, Bircher A, Atanaskovic M, Demoly P, K Tanno L, Terreehorst I, Laguna JJ, Romano A, Guéant JL | title = Genetic variants associated with drugs-induced immediate hypersensitivity reactions: a PRISMA-compliant systematic review | journal = Allergy | volume = 71 | issue = 4 | pages = 443–462 | year = 2016 | pmid = 26678823 | doi = 10.1111/all.12821 | url = https://archive-ouverte.unige.ch/unige:83795/ATTACHMENT01 | doi-access = free }}</ref><ref name="pmid8683135">{{cite journal | vauthors = O'Flaherty JT, Kuroki M, Nixon AB, Wijkander J, Yee E, Lee SL, Smitherman PK, Wykle RL, Daniel LW | title = 5-Oxo-eicosatetraenoate is a broadly active, eosinophil-selective stimulus for human granulocytes | journal = Journal of Immunology | volume = 157 | issue = 1 | pages = 336–342 | year = 1996 | doi = 10.4049/jimmunol.157.1.336 | pmid = 8683135 | s2cid = 35264541 | doi-access = free }}</ref><ref name="pmid27333777">{{cite journal | vauthors = Schauberger E, Peinhaupt M, Cazares T, Lindsley AW | title = Lipid Mediators of Allergic Disease: Pathways, Treatments, and Emerging Therapeutic Targets | journal = Current Allergy and Asthma Reports | volume = 16 | issue = 7 | pages = 48 | year = 2016 | pmid = 27333777 | doi = 10.1007/s11882-016-0628-3 | pmc = 5515624 }}</ref>
=== Hypersensitivity reactions ===
ALOX5 contributes to non-allergic [[NSAID hypersensitivity reactions]] of the [[respiratory system]] and [[Human skin|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.<ref name="pmid25572555" /><ref name="Haeggström_2011" /><ref name="pmid25818037">{{cite journal | vauthors = Barros R, Moreira A, Padrão P, Teixeira VH, Carvalho P, Delgado L, Lopes C, Severo M, Moreira P | title = Dietary patterns and asthma prevalence, incidence and control | journal = Clinical & Experimental Allergy | volume = 45 | issue = 11 | pages = 1673–1680 | year = 2015 | pmid = 25818037 | doi = 10.1111/cea.12544 | s2cid = 32499209 }}</ref>
=== ALOX5-inhibiting drugs ===
{{Main|Arachidonate 5-lipoxygenase inhibitor}}
The tissue, animal model, and animal and human genetic studies cited above implicate ALOX5 in a wide range of diseases:
* excessive inflammatory responses to [[pathogen]]s, trauma, burns, and other forms of tissue injury (see {{slink|Inflammation|Causes}})
* chronic inflammatory conditions such as:
** [[rheumatoid arthritis]]
** [[atherosclerosis]]
** [[inflammatory bowel disease]]
** [[autoimmune disease]]s
** [[Alzheimer's disease]]
(see {{slink|Inflammation|Disorders}})
* [[allergy]] and [[allergic inflammation]] reactions such as:
** allergic [[rhinitis]]
** [[conjunctivitis]]
** [[asthma]]
** [[rash]]es
** [[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.<ref name="Haeggström_2011" /><ref name="pmid23987187">{{cite journal | vauthors = Fanning LB, Boyce JA | title = Lipid mediators and allergic diseases | journal = Annals of Allergy, Asthma & Immunology | volume = 111 | issue = 3 | pages = 155–162 | year = 2013 | pmid = 23987187 | pmc = 4088989 | doi = 10.1016/j.anai.2013.06.031 }}</ref> 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 {{slink|Clinical trial|Phases}}) combining it with [[imatinib]] for treating [[chronic myeloid leukemia]].<ref name="pmid23953428">{{cite journal | vauthors = Steinhilber D, Hofmann B | title = Recent advances in the search for novel 5-lipoxygenase inhibitors | journal = Basic & Clinical Pharmacology & Toxicology | volume = 114 | issue = 1 | pages = 70–77 | year = 2014 | pmid = 23953428 | doi = 10.1111/bcpt.12114 | doi-access = free }}</ref><ref name="pmid26385352">{{cite journal | vauthors = Cingi C, Muluk NB, Ipci K, Şahin E | title = Antileukotrienes in upper airway inflammatory diseases | journal = Current Allergy and Asthma Reports | volume = 15 | issue = 11 | page = 64 | year = 2015 | pmid = 26385352 | doi = 10.1007/s11882-015-0564-7 | s2cid = 38854822 }}</ref>
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 {{slink|Zileuton|Contraindications and warnings}}).<ref name="pmid23953428" /> Given these deficiencies, other drugs targeting ALOX5 are under study.
'''[[Flavocoxid]]''' is a proprietary blend of purified plant derived bioflavonoids including [[Baicalin]] and [[Catechin]]s. 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&nbsp;mg under the commercial name Limbrel. However, in [[clinical trial]]s 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.<ref>{{cite web | url = https://livertox.nlm.nih.gov/Flavocoxid.htm | title = Flavocoxid Drug Record | work = LiverTox | publisher = United States National Library of Medicine | access-date = 2016-08-22 | archive-date = 2019-08-19 | archive-url = https://web.archive.org/web/20190819184243/https://livertox.nlm.nih.gov/Flavocoxid.htm | url-status = dead }}</ref>
'''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).<ref name="pmid23953428" /><ref>{{ClinicalTrialsGov|NCT00404313|The Effect of MK0633 in Patients With Chronic Asthma}}</ref> '''PF-4191834'''<ref>{{cite web | url = http://www.medkoo.com/products/7366 | title = PF-4191834 | publisher = MedKoo Biosciences, Inc. }}</ref> has completed phase II studies for the treatment of asthma (NCT00723021).<ref name="pmid23953428" />
'''[[Hyperforin]]''', an active constituent of the herb [[Hypericum perforatum|St John's wort]], is active at micro[[molar concentration]]s in inhibiting ALOX5.<ref name="pmid12445866">{{cite journal | vauthors = Albert D, Zündorf I, Dingermann T, Müller WE, Steinhilber D, Werz O | title = Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase | journal = Biochemical Pharmacology | volume = 64 | issue = 12 | pages = 1767–1775 | date = Dec 2002 | pmid = 12445866 | doi = 10.1016/s0006-2952(02)01387-4 }}</ref> 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.<ref name="pmid24368834">{{cite journal | vauthors = Blazevic T, Schaible AM, Weinhäupl K, Schachner D, Nikels F, Weinigel C, Barz D, Atanasov AG, Pergola C, Werz O, Dirsch VM, Heiss EH | title = Indirubin-3'-monoxime exerts a dual mode of inhibition towards leukotriene-mediated vascular smooth muscle cell migration | journal = Cardiovascular Research | volume = 101 | issue = 3 | pages = 522–532 | date = Mar 2014 | pmid = 24368834 | pmc = 3928003 | doi = 10.1093/cvr/cvt339 }}</ref> In addition, [[curcumin]], a constituent of [[turmeric]], is a 5-LO inhibitor as defined by [[in vitro]] studies of the enzyme.<ref name="MEDRS review">{{cite journal | vauthors = Bishayee K, Khuda-Bukhsh AR | title = 5-lipoxygenase antagonist therapy: a new approach towards targeted cancer chemotherapy | journal = Acta Biochimica et Biophysica Sinica | volume = 45 | issue = 9 | pages = 709–719 | date = Sep 2013 | pmid = 23752617 | doi = 10.1093/abbs/gmt064 | doi-access = free }}</ref>
'''Acetyl-keto-beta-boswellic acid ([[Boswellic acid#Structure|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.<ref name="Simon Kirste 2009">{{cite thesis | vauthors = Kirste S | year = 2009 | title = Antiödematöse Wirkung von Boswellia serrata auf das Strahlentherapie-assoziierte Hirnödem | trans-title = Anti-edematous effect of Boswellia serrata on radiation therapy – associated brain edema | language = de | degree = Ph.D. | publisher = University Freiburg | location = Breisgau, Germany | url = https://d-nb.info/101045384X/34 }}</ref><ref name="pmid21287538">{{cite journal | vauthors = Kirste S, Treier M, Wehrle SJ, Becker G, Abdel-Tawab M, Gerbeth K, Hug MJ, Lubrich B, Grosu AL, Momm F | display-authors = 6 | title = Boswellia serrata acts on cerebral edema in patients irradiated for brain tumors: a prospective, randomized, placebo-controlled, double-blind pilot trial | journal = Cancer | volume = 117 | issue = 16 | pages = 3788–3795 | date = August 2011 | pmid = 21287538 | doi = 10.1002/cncr.25945 | s2cid = 11283379 | doi-access = free }}</ref>
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 antagonist]]s 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<ref name="pmid24313690" /> and also may be useful for treating acquired childhood [[sleep apnea]] due to adenotonsillar hypertrophy (see {{slink|Acquired non-inflammatory myopathy|Diet and Trauma Induced Myopathy}}).<ref name="pmid26980339">{{cite journal | vauthors = Kar M, Altıntoprak N, Muluk NB, Ulusoy S, Bafaqeeh SA, Cingi C | title = Antileukotrienes in adenotonsillar hypertrophy: a review of the literature | journal = European Archives of Oto-Rhino-Laryngology | volume = 273| issue = 12| pages = 4111–4117| year = 2016 | pmid = 26980339 | doi = 10.1007/s00405-016-3983-8 | s2cid = 31311115 }}</ref>
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 antagonist]]s have proven inferior to [[corticosteroid]]s 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.<ref name="pmid25316652">{{cite journal | vauthors = Kuhn H, Banthiya S, van Leyen K | title = Mammalian lipoxygenases and their biological relevance | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | volume = 1851 | issue = 4 | pages = 308–330 | year = 2015 | pmid = 25316652 | pmc = 4370320 | doi = 10.1016/j.bbalip.2014.10.002 }}</ref>
== 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 [[promoter (genetics)|promoter]] in the human ''ALOX5'' gene commonly possess five GGGCCGG repeats which bind the [[Transcription factor Sp1|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.<ref name="pmid19665766">{{cite journal | vauthors = Tantisira KG, Drazen JM | title = Genetics and pharmacogenetics of the leukotriene pathway | journal = The Journal of Allergy and Clinical Immunology | volume = 124 | issue = 3 | pages = 422–427 | year = 2009 | pmid = 19665766 | pmc = 2794036 | doi = 10.1016/j.jaci.2009.06.035 }}</ref> These data suggest that ALOX5 may contribute to dampening the severity of asthma, possibly by metabolizing PUFA to [[specialized pro-resolving mediators]].<ref name="pmid26546247">{{cite journal | vauthors = Duvall MG, Levy BD | title = DHA- and EPA-derived resolvins, protectins, and maresins in airway inflammation | journal = European Journal of Pharmacology | volume = 785 | pages = 144–155 | year = 2016 | pmid = 26546247 | doi = 10.1016/j.ejphar.2015.11.001 | pmc=4854800}}</ref> [[Single nucleotide polymorphism]] differences in the genes that promote ALOX5 activity (i.e. [[5-lipoxygenase-activating protein]]), metabolize the initial product of ALOX5, 5''S''-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.<ref name="pmid19665766" />
=== NSAID-induced non-allergic reactions ===
[[Aspirin]] and other [[non-steroidal anti-inflammatory drug]]s (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 response]]s 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]]).<ref name="pmid24117484">{{cite journal | vauthors = Kowalski ML, Asero R, Bavbek S, Blanca M, Blanca-Lopez N, Bochenek G, Brockow K, Campo P, Celik G, Cernadas J, Cortellini G, Gomes E, Niżankowska-Mogilnicka E, Romano A, Szczeklik A, Testi S, Torres MJ, Wöhrl S, Makowska J | title = Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs | journal = Allergy | volume = 68 | issue = 10 | pages = 1219–1232 | year = 2013 | pmid = 24117484 | doi = 10.1111/all.12260 | s2cid = 32169451 }}</ref> The [[Gene polymorphism|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,<ref>{{cite web | url = https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=4948672 | title = Reference SNP (refSNP) Cluster Report: rs4948672 | work = NCBI dbSNP}}</ref> rs1565096,<ref>{{cite web | url = https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1565096 | title = Reference SNP (refSNP) Cluster Report: rs1565096 | work = NCBI dbSNP}}</ref> and rs7894352,<ref>{{cite web | url = https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=7894352 | title = Reference SNP (refSNP) Cluster Report: rs7894352 | work = NCBI dbSNP}}</ref> are associated with NSAID-induced cutaneous reactions in Spanish patients.<ref name="pmid26678823" />
=== 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.<ref name="pmid14702425">{{cite journal | vauthors = Dwyer JH, Allayee H, Dwyer KM, Fan J, Wu H, Mar R, Lusis AJ, Mehrabian M | title = Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis | journal = The New England Journal of Medicine | volume = 350 | issue = 1 | pages = 29–37 | year = 2004 | pmid = 14702425 | doi = 10.1056/NEJMoa025079 | doi-access = free }}</ref>
== See also ==
[[Arachidonate 5-lipoxygenase inhibitor]]
== References ==
{{Reflist|33em}}
== Further reading ==
{{Refbegin|33em}}
* {{cite journal | vauthors = Rådmark OP | title = The molecular biology and regulation of 5-lipoxygenase | journal = Am. J. Respir. Crit. Care Med. | volume = 161 | issue = 2 Pt 2 | pages = S11–5 | year = 2000 | pmid = 10673219 | doi = 10.1164/ajrccm.161.supplement_1.ltta-3 }}
* {{cite book | vauthors = Hammarberg T, Reddy KV, Persson B, Rådmark O | title = Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation, and Radiation Injury, 5 | chapter = Calcium Binding to 5-Lipoxygenase | volume = 507 | pages = 117–121 | year = 2002 | pmid = 12664574 | doi = 10.1007/978-1-4615-0193-0_19 | isbn = 978-0-306-47283-1 | series = Advances in Experimental Medicine and Biology | veditors=  Honn KV, Marnett LJ, Nigam S, Dennis E, Serhan C | publisher= Springer }}
* {{cite journal | vauthors = Ishii S, Noguchi M, Miyano M, Matsumoto T, Noma M | title = Mutagenesis studies on the amino acid residues involved in the iron-binding and the activity of human 5-lipoxygenase | journal = Biochem. Biophys. Res. Commun. | volume = 182 | issue = 3 | pages = 1482–1490 | year = 1992 | pmid = 1540191 | doi = 10.1016/0006-291X(92)91901-2 }}
* {{cite journal | vauthors = Nguyen T, Falgueyret JP, Abramovitz M, Riendeau D | title = Evaluation of the role of conserved His and Met residues among lipoxygenases by site-directed mutagenesis of recombinant human 5-lipoxygenase | journal = J. Biol. Chem. | volume = 266 | issue = 32 | pages = 22057–22062 | year = 1991 | doi = 10.1016/S0021-9258(18)54744-X | pmid = 1939225 | doi-access = free }}
* {{cite journal | vauthors = Hoshiko S, Rådmark O, Samuelsson B | title = Characterization of the human 5-lipoxygenase gene promoter | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 87 | issue = 23 | pages = 9073–9077 | year = 1990 | pmid = 2251250 | pmc = 55106 | doi = 10.1073/pnas.87.23.9073 | bibcode = 1990PNAS...87.9073H | doi-access = free }}
* {{cite journal | vauthors = Matsumoto T, Funk CD, Rådmark O, Höög JO, Jörnvall H, Samuelsson B | title = Molecular cloning and amino acid sequence of human 5-lipoxygenase | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 85 | issue = 1 | pages = 26–30 | year = 1988 | pmid = 2829172 | pmc = 279474 | doi = 10.1073/pnas.85.1.26 | bibcode = 1988PNAS...85...26M | doi-access = free }}
* {{cite journal | vauthors = Rouzer CA, Kargman S | title = Translocation of 5-lipoxygenase to the membrane in human leukocytes challenged with ionophore A23187 | journal = J. Biol. Chem. | volume = 263 | issue = 22 | pages = 10980–10988 | year = 1988 | doi = 10.1016/S0021-9258(18)38066-9 | pmid = 3134355 | doi-access = free }}
* {{cite journal | vauthors = Dixon RA, Jones RE, Diehl RE, Bennett CD, Kargman S, Rouzer CA | title = Cloning of the cDNA for human 5-lipoxygenase | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 85 | issue = 2 | pages = 416–420 | year = 1988 | pmid = 3422434 | pmc = 279559 | doi = 10.1073/pnas.85.2.416 | bibcode = 1988PNAS...85..416D | doi-access = free }}
* {{cite journal | vauthors = Jakobsson PJ, Shaskin P, Larsson P, Feltenmark S, Odlander B, Aguilar-Santelises M, Jondal M, Biberfeld P, Claesson HE | title = Studies on the regulation and localization of 5-lipoxygenase in human B-lymphocytes | journal = Eur. J. Biochem. | volume = 232 | issue = 1 | pages = 37–46 | year = 1995 | pmid = 7556168 | doi = 10.1111/j.1432-1033.1995.tb20778.x | doi-access = free }}
* {{cite journal | vauthors = Janssen-Timmen U, Vickers PJ, Wittig U, Lehmann WD, Stark HJ, Fusenig NE, Rosenbach T, Rådmark O, Samuelsson B, Habenicht AJ | title = Expression of 5-lipoxygenase in differentiating human skin keratinocytes | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 92 | issue = 15 | pages = 6966–6970 | year = 1995 | pmid = 7624354 | pmc = 41452 | doi = 10.1073/pnas.92.15.6966 | bibcode = 1995PNAS...92.6966J | doi-access = free }}
* {{cite journal | vauthors = Lepley RA, Fitzpatrick FA | title = 5-Lipoxygenase contains a functional Src homology 3-binding motif that interacts with the Src homology 3 domain of Grb2 and cytoskeletal proteins | journal = J. Biol. Chem. | volume = 269 | issue = 39 | pages = 24163–24168 | year = 1994 | doi = 10.1016/S0021-9258(19)51063-8 | pmid = 7929073 | doi-access = free }}
* {{cite journal | vauthors = Shaw KJ, Ng C, Kovacs BW | title = Cyclooxygenase gene expression in human endometrium and decidua | journal = Prostaglandins Leukot. Essent. Fatty Acids | volume = 50 | issue = 5 | pages = 239–243 | year = 1994 | pmid = 8066098 | doi = 10.1016/0952-3278(94)90160-0 }}
* {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1–2 | pages = 171–174 | year = 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
* {{cite journal | vauthors = Woods JW, Evans JF, Ethier D, Scott S, Vickers PJ, Hearn L, Heibein JA, Charleson S, Singer II | title = 5-lipoxygenase and 5-lipoxygenase-activating protein are localized in the nuclear envelope of activated human leukocytes | journal = J. Exp. Med. | volume = 178 | issue = 6 | pages = 1935–1946 | year = 1993 | pmid = 8245774 | pmc = 2191287 | doi = 10.1084/jem.178.6.1935 }}
* {{cite journal | vauthors = Mancini JA, Li C, Vickers PJ | title = 5-Lipoxygenase activity in the human pancreas | journal = J Lipid Mediat | volume = 8 | issue = 3 | pages = 145–150 | year = 1993 | pmid = 8268460 }}
* {{cite journal | vauthors = VanderNoot VA, Fitzpatrick FA | title = Competitive binding assay of src homology domain 3 interactions between 5-lipoxygenase and growth factor receptor binding protein 2 | journal = Anal. Biochem. | volume = 230 | issue = 1 | pages = 108–114 | year = 1995 | pmid = 8585605 | doi = 10.1006/abio.1995.1444 }}
* {{cite journal | vauthors = Brock TG, McNish RW, Bailie MB, Peters-Golden M | title = Rapid import of cytosolic 5-lipoxygenase into the nucleus of neutrophils after in vivo recruitment and in vitro adherence | journal = J. Biol. Chem. | volume = 272 | issue = 13 | pages = 8276–8280 | year = 1997 | pmid = 9079648 | doi = 10.1074/jbc.272.13.8276 | doi-access = free }}
* {{cite journal | vauthors = Nassar GM, Montero A, Fukunaga M, Badr KF | title = Contrasting effects of proinflammatory and T-helper lymphocyte subset-2 cytokines on the 5-lipoxygenase pathway in monocytes | journal = Kidney Int. | volume = 51 | issue = 5 | pages = 1520–1528 | year = 1997 | pmid = 9150468 | doi = 10.1038/ki.1997.209 | doi-access = free }}
* {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1–2 | pages = 149–156 | year = 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
{{Refend}}
== External links ==
* {{MeshName|Arachidonate+5-Lipoxygenase}}
* {{UCSC gene info|ALOX5}}
{{Iron-binding proteins}}
{{Metabolism of complex lipids}}
{{Leukotrienergics}}
{{Monooxygenases}}
{{Enzymes}}
{{Portal bar|Biology|border=no}}
[[Category:EC 1.13.11]]
[[Category:Enzymes]]
[[Category:Eicosanoids]]
[[Category:Lipid metabolism]]
[[Category:Peripheral membrane proteins]]