Arachidonate 5-lipoxygenase, also known as ALOX5, 5-lipoxygenase, 5-LOX, or 5-LO, is a non-
heme
Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver.
In biochemical terms, heme is a coordination complex "consisti ...
iron-containing
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
(EC 1.13.11.34) that in humans is encoded by the ''ALOX5''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
Arachidonate 5-lipoxygenase is a member of the
lipoxygenase
Lipoxygenases () are a family of (non-heme) iron-containing enzymes most of which catalyze the dioxygenation of polyunsaturated fatty acids in lipids containing a cis,cis-1,4- pentadiene into cell signaling agents that serve diverse roles as aut ...
family of enzymes. It transforms essential fatty acids (
EFA
EFA may refer to: England Football Association
Arts
* European Film Academy, a trade organisation
* European Film Awards, organized by the European Film Academy
* European Festivals Association, an arts festival organisation
Commerce
* Electri ...
) substrates into
leukotrienes
Leukotrienes are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxygenase.
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
base pair
A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...
s (kb) on chromosome 10 (all other human lipoxygenases are clustered together on chromosome 17), is composed of 14
exons
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
divided by 13
introns
An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene ...
encoding the mature 78
kilodalton
The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at ...
(kD) ALOX5 protein consisting of 673 amino acids. The
gene promoter
In genetics, a promoter is a sequence of DNA to which proteins bind to initiate transcription of a single RNA transcript from the DNA downstream of the promoter. The RNA transcript may encode a protein (mRNA), or can have a function in and of ...
region of ALOX5 contains 8
GC box In molecular biology, a GC box, also known as a GSG box, is a distinct pattern of nucleotides found in the promoter region of some eukaryotic genes. The GC box is upstream of the TATA box, and approximately 110 bases upstream from the transcription ...
es but lacks
TATA box
In molecular biology, the TATA box (also called the Goldberg–Hogness box) is a sequence of DNA found in the core promoter region of genes in archaea and eukaryotes. The bacterial homolog of the TATA box is called the Pribnow box which has ...
es or
CAT box
The cat (''Felis catus'') is a domestic species of small carnivorous mammal. It is the only domesticated species in the family Felidae and is commonly referred to as the domestic cat or house cat to distinguish it from the wild members o ...
es and thus resembles the gene promoters of typical
housekeeping gene
In molecular biology, housekeeping genes are typically constitutive genes that are required for the maintenance of basic cellular function, and are expressed in all cells of an organism under normal and patho-physiological conditions. Although ...
s. Five of the 8 GC boxes are arranged in tandem and are recognized by the transcription factors
Sp1 and
Egr-1
EGR-1 (Early growth response protein 1) also known as ZNF268 (zinc finger protein 268) or NGFI-A (nerve growth factor-induced protein A) is a protein that in humans is encoded by the ''EGR1'' gene.
EGR-1 is a mammalian transcription factor. It wa ...
. 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.
Expression
Cells primarily involved in regulating
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
,
allergy
Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...
, and other
immune response
An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which could ...
s, e.g.
neutrophils
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...
,
eosinophil
Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...
s,
basophil
Basophils are a type of white blood cell. Basophils are the least common type of granulocyte, representing about 0.5% to 1% of circulating white blood cells. However, they are the largest type of granulocyte. They are responsible for inflammator ...
s,
monocyte
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also inf ...
s,
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s,
mast cell
A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a par ...
s,
dendritic cell
Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. ...
s, and
B-lymphocyte
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
s express ALOX5.
Platelet
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
s,
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
s, and
erythrocyte
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
s are ALOX5-negative. In skin,
Langerhans cell
A Langerhans cell (LC) is a tissue-resident macrophage of the skin. These cells contain organelles called Birbeck granules. They are present in all layers of the epidermis and are most prominent in the stratum spinosum. They also occur in the ...
s strongly express ALOX5.
Fibroblasts
A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells o ...
,
smooth muscle
Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...
cells and
endothelial cell
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
s express low levels of ALOX5.
Up-regulation of ALOX5 may occur during the maturation of
leukocyte
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
s and in human neutrophils treated with
granulocyte macrophage colony-stimulating factor
Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts th ...
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.
Studies with cultured human cells have found that there are a large number of ALOX5
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
splice variants due to
alternative splicing
Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...
. 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.
Biochemistry
Human ALOX5 is a soluble, monomeric
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
consisting of 673
amino acids
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
with a
molecular weight
A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...
of ~78
kDa
The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...
. Structurally, ALOX5 possesses:
* A
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
catalytic domain (residues 126–673)
* An
N-terminal
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
C2-like domain
Discoidin domain (also known as F5/8 type C domain, or C2-like domain) is major protein domain of many blood coagulation factors.
Blood coagulation factors Factor V, V and Factor VIII, VIII contain a C-terminal, twice repeated, domain of about 1 ...
which promotes its binding to ligand substrates, Ca
2+, cellular phospholipid membranes, Coactin-like protein (
COL1
Type I collagen is the most abundant collagen of the human body. It forms large, eosinophilic fibers known as collagen fibers.
It is present in scar tissue, the end product when tissue heals by repair, as well as tendons, ligaments, the endom ...
), and
Dicer
Dicer, also known as endoribonuclease Dicer or helicase with RNase motif, is an enzyme that in humans is encoded by the gene. Being part of the RNase III family, Dicer cleaves double-stranded RNA (dsRNA) and pre-microRNA (pre-miRNA) into short ...
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
Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms of ...
(ATP) binding site; ATP is crucial for ALOX5's metabolic activity
* A
proline
Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...
-rich region (residues 566–577), sometimes termed a SH3-binding domain, which promotes its binding to proteins with
SH3 domain
The SRC Homology 3 Domain (or SH3 domain) is a small protein domain of about 60 amino acid residues. Initially, SH3 was described as a conserved sequence in the viral adaptor protein v-Crk. This domain is also present in the molecules of phos ...
s such as
Grb2 and may thereby link the enzyme's regulation to
tyrosine kinase receptors
Receptor tyrosine kinases (RTKs) are the high-dissociation constant#Protein-ligand binding, affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the hu ...
.
The enzyme possesses two catalytic activities as illustrated by its metabolism of
arachidonic acid. ALOX5's
dioxygenase
Dioxygenases are oxidoreductase enzymes. Aerobic life, from simple single-celled bacteria species to complex eukaryotic organisms, has evolved to depend on the oxidizing power of dioxygen in various metabolic pathways. From energetic adenosine tri ...
activity adds a
hydroperoxyl
The hydroperoxyl radical, also known as the hydrogen superoxide, is the protonated form of superoxide with the chemical formula HO2. This species plays an important role in the atmosphere and as a reactive oxygen species in cell biology.
Struc ...
(i.e. HO
2) 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). The 5''S''-HpETE intermediate may then be released by the enzyme and rapidly reduced by cellular
glutathione peroxidase
Glutathione peroxidase (GPx) () is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage. The biochemical function of glutathione peroxidase is to reduce lipid h ...
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
In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale for ...
, 5''S'',6''S''-hydroxy-6''E'',8''Z'',11''Z'',14''Z''-eicosatetraenoic acid (i.e.
LTA4
Leukotriene A4 (LTA4) is a leukotriene, and is the precursor for the productions of LTB4 ( leukotriene B)) and LTC4 (leukotriene C4).
Biosynthesis of Leukotriene A4
Following the biosynthesis of eicosanoid, triggered as a result of infection o ...
). LTA4 is then acted on by a separate, soluble enzyme,
Leukotriene-A4 hydrolase
Leukotriene A4 hydrolase, also known as LTA4H is a human gene. The protein encoded by this gene is a bifunctional enzyme () which converts leukotriene A4 to leukotriene B4 and acts as an aminopeptidase.
Function
This enzyme belongs to the family ...
, to form the dihydroxyl product,
Leukotriene B4
Leukotriene B4 (LTB4) is a leukotriene involved in inflammation. It has been shown to promote insulin resistance in obese mice.
Biochemistry
Leukotriene B4 (LTB4) is a leukotriene involved in inflammation. It is produced from leukocytes in r ...
(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
Leukotriene C4 synthase is an enzyme that in humans is encoded by the ''LTC4S'' gene.
The protein encoded by this gene, LTC4S (or glutathione S-transferase II) is an enzyme that converts leukotriene A4 and glutathione to create leukotriene C4. Th ...
or microsomal
glutathione S-transferase
Glutathione ''S''-transferases (GSTs), previously known as ligandins, are a family of eukaryotic and prokaryotic phase II metabolic isozymes best known for their ability to catalyze the conjugation of the reduced form of glutathione (GSH) ...
2 (
MGST2
Microsomal glutathione S-transferase 2 is an enzyme that in humans is encoded by the ''MGST2'' gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''ge ...
), which bind the sulfur of cysteine's thio (i.e. SH) residue in the tripeptide
glutamate
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
-
cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, sometime ...
-
glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
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
Gamma-glutamyltransferase (also γ-glutamyltransferase, GGT, gamma-GT, gamma-glutamyl transpeptidase; ) is a transferase (a type of enzyme) that catalyzes the transfer of gamma-glutamyl functional groups from molecules such as glutathione to ...
and a dipeptidase to form sequentially
LTD4
Leukotriene D4 (LTD4) is one of the leukotrienes. Its main function in the body is to induce the contraction of smooth muscle, resulting in bronchoconstriction and vasoconstriction. It also increases vascular permeability. LTD4 is released by bas ...
and
LTE4
Leukotriene E4 (LTE4) is a cysteinyl leukotriene involved in inflammation. It is known to be produced by several types of white blood cells, including eosinophils, mast cells, tissue macrophages, and basophils, and recently was also found to be ...
.
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
serine
Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...
663, 523, and/or 271 by
Mitogen-activated protein kinase
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
s,
S6 kinase,
protein kinase A
In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, including regulatio ...
(PKA),
protein kinase C
In cell biology, Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...
,
Cdc2
Cyclin-dependent kinase 1 also known as CDK1 or cell division cycle protein 2 homolog is a highly conserved protein that functions as a serine/threonine protein kinase, and is a key player in cell cycle regulation. It has been highly studied in th ...
, and/or a Ca
2+/calmodulin-dependent protein kinase; b) moves to bind with phospholipids in the
nuclear membrane
The nuclear envelope, also known as the nuclear membrane, is made up of two lipid bilayer membranes that in eukaryotic cells surround the nucleus, which encloses the genetic material.
The nuclear envelope consists of two lipid bilayer membra ...
and, probably,
endoplasmic reticulum
The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough 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
2+ 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 factor
Chemotaxis (from '' chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemica ...
s on leukocytes. Rises in cytosolic Ca
2+, ALOX5's movement to membranes, and ALOX5's interaction with FLAP are critical to the physiological activation of the enzyme.
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.
In addition to its activation, ALOX5 must gain access to its
polyunsaturated fatty acid
Polyunsaturated fatty acids (PUFAs) are fatty acids that contain more than one double bond in their backbone. This class includes many important compounds, such as essential fatty acids and those that give drying oils their characteristic proper ...
(PUFA) substrates, which commonly are bound in an ester linkage to the ''sn''2 position of membrane phospholipids (see
phospholipid
Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
), in order to form biologically active products. This is accomplished by a large family of
phospholipase A2
The enzyme phospholipase A2 (EC 3.1.1.4, PLA2, systematic name phosphatidylcholine 2-acylhydrolase) catalyse the cleavage of fatty acids in position 2 of phospholipids, hydrolyzing the bond between the second fatty acid “tail” and the glyce ...
(PLA
2) enzymes. The cytosolic PLA
2 set (i.e. cPLA
2s) of PLA
2 enzymes (cPLA2; see
Phospholipase A2#Cytosolic phospholipases A2) 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
2+ which triggers cPLA
2s, particularly the α isoform (cPLA
2α), 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
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
s (MAPK) which in turn stimulates the activity of cPLA
2α by phosphorylating it on ser-505 (other cell types may activate this or other cPLA
2 isoforms using other kinases which phosphorylate them on different serine residues). These two events allow cPLA
2s to release PUFA esterified to membrane phospholipids to FLAP which then presents them to ALOX5 for their metabolism.
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)
In molecular biology, molecular chaperones are proteins that assist the conformational folding or unfolding of large proteins or macromolecular protein complexes. There are a number of classes of molecular chaperones, all of which function to assi ...
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
2+, this binding also alters the relative levels of hydroperoxy versus epoxide (see arachidonic acid section below) products made by ALOX5.
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.
The presence of certain
diacylglycerol
A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. DAGs can act as s ...
s such as 1-oleoyl-2-acetylglycerol, 1-hexadecyl-2-acetyl-''sn''-glycerol, and 1-''O''-hexadecyl-2-acetyl-''sn''-glycerol, and 1,2-dioctanoyl-''sn''-glycerol but not 1-steroyl-2-arachidonyl-''sn''-glyerol increase the catalytic activity of ALOX5 in vitro.
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
omega-6 fatty acid
Omega-6 fatty acids (also referred to as ω-6 fatty acids or ''n''-6 fatty acids) are a family of polyunsaturated fatty acids that have in common a final carbon-carbon double bond in the ''n''-6 position, that is, the sixth bond, counting from ...
,
Arachidonic acid (AA, i.e. 5''Z'',8''Z'',11''Z'',15''Z''-eicosatrienoic acid), to 5-hydroperoxyeicosatetraenoic acid (
5-HpETE) which is then rapidly converted to physiologically and pathologically important products. Ubiquitous cellular
glutathione peroxidase
Glutathione peroxidase (GPx) () is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage. The biochemical function of glutathione peroxidase is to reduce lipid h ...
s (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
Leukotriene A4 (LTA4) is a leukotriene, and is the precursor for the productions of LTB4 ( leukotriene B)) and LTC4 (leukotriene C4).
Biosynthesis of Leukotriene A4
Following the biosynthesis of eicosanoid, triggered as a result of infection o ...
, which is then either rapidly converted to leukotriene B4 (
LTB4
Leukotriene B4 (LTB4) is a leukotriene involved in inflammation. It has been shown to promote insulin resistance in obese mice.
Biochemistry
Leukotriene B4 (LTB4) is a leukotriene involved in inflammation. It is produced from leukocytes in respon ...
) by
Leukotriene-A4 hydrolase
Leukotriene A4 hydrolase, also known as LTA4H is a human gene. The protein encoded by this gene is a bifunctional enzyme () which converts leukotriene A4 to leukotriene B4 and acts as an aminopeptidase.
Function
This enzyme belongs to the family ...
(LTA4H) or to leukotriene C4 (
LTC4
Leukotriene C4 (LTC4) is a leukotriene. LTC4 has been extensively studied in the context of allergy and asthma. In cells of myeloid origin such as mast cells, its biosynthesis is orchestrated by translocation to the nuclear envelope along with c ...
) by
LTC4 synthase
Leukotriene C4 synthase is an enzyme that in humans is encoded by the ''LTC4S'' gene.
The protein encoded by this gene, LTC4S (or glutathione S-transferase II) is an enzyme that converts leukotriene A4 and glutathione to create leukotriene C4. Th ...
(LTC4S); LTC4 exits its cells of origin through the
MRP1 transporter (ABCC1) and is rapidly converted to
LTD4
Leukotriene D4 (LTD4) is one of the leukotrienes. Its main function in the body is to induce the contraction of smooth muscle, resulting in bronchoconstriction and vasoconstriction. It also increases vascular permeability. LTD4 is released by bas ...
and then to
LTE4
Leukotriene E4 (LTE4) is a cysteinyl leukotriene involved in inflammation. It is known to be produced by several types of white blood cells, including eosinophils, mast cells, tissue macrophages, and basophils, and recently was also found to be ...
) by cell surface-attached gamma-glutamyltransferase and dipeptidase peptidase enzymes. In another pathway, ALOX5 may act in series with a second lipoxygenase enzyme,
ALOX15
ALOX15 (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically importa ...
, to metabolize AA to
lipoxin
A lipoxin (LX or Lx), an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolvin ...
A4 (LxA4) and LxB4 (see
Specialized pro-resolving mediators#Lipoxins).
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-oxoETE may contribute to the
innate immune response as leukocyte
chemotactic factor
Chemotaxis (from '' chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemica ...
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
Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecu ...
s (see
5-HETE and
LTB4
Leukotriene B4 (LTB4) is a leukotriene involved in inflammation. It has been shown to promote insulin resistance in obese mice.
Biochemistry
Leukotriene B4 (LTB4) is a leukotriene involved in inflammation. It is produced from leukocytes in respon ...
). 5-Oxo-ETE is a particularly potent chemotactic factor for and activator of
eosinophil
Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...
s and may thereby contribute to eosinophil-based allergic reactions and diseases (see
5-oxo-eicosatetraenoic acid).
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
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
.
ALOX5 and its LTB4 metabolite as well as this metabolite's
BLT
A BLT is a type of sandwich, named for the initials of its primary ingredients, bacon, lettuce, and tomato. It can be made with varying recipes according to personal preference. Simple variants include using different types of lettuce, toastin ...
1 and
BLT2 receptors have also been shown to promote the growth of various types of human cancer cell lines in culture.
LTC4, LTD4, and LTE4 contribute to allergic airways reactions such as
asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...
, certain non-allergic hypersensitivity airways reactions, and other lung diseases involving
bronchoconstriction
Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath.
Causes
The condition has a number of causes, the most common be ...
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
Rhinitis, also known as coryza, is irritation and inflammation of the mucous membrane inside the nose. Common symptoms are a stuffy nose, runny nose, sneezing, and post-nasal drip.
The inflammation is caused by viruses, bacteria, irritants o ...
,
conjunctivitis
Conjunctivitis, also known as pink eye, is inflammation of the conjunctiva, outermost layer of the white part of the eye and the inner surface of the eyelid. It makes the eye appear pink or reddish. Pain, burning, scratchiness, or itchiness may ...
, and
urticaria
Hives, also known as urticaria, is a kind of skin rash with red, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and does not leave any long-lasti ...
(see
LTC4
Leukotriene C4 (LTC4) is a leukotriene. LTC4 has been extensively studied in the context of allergy and asthma. In cells of myeloid origin such as mast cells, its biosynthesis is orchestrated by translocation to the nuclear envelope along with c ...
,
LTD4
Leukotriene D4 (LTD4) is one of the leukotrienes. Its main function in the body is to induce the contraction of smooth muscle, resulting in bronchoconstriction and vasoconstriction. It also increases vascular permeability. LTD4 is released by bas ...
, and
LTE4
Leukotriene E4 (LTE4) is a cysteinyl leukotriene involved in inflammation. It is known to be produced by several types of white blood cells, including eosinophils, mast cells, tissue macrophages, and basophils, and recently was also found to be ...
).
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.
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
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
(see
specialized pro-resolving mediators
Specialized pro-resolving mediators (SPM, also termed specialized proresolving mediators) are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of ...
and
lipoxin
A lipoxin (LX or Lx), an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolvin ...
s).
Mead acid
Mead acid
Mead acid is an omega-9 fatty acid, first characterized by James F. Mead. As with some other omega-9 polyunsaturated fatty acids, animals can make Mead acid ''de novo''. Its elevated presence in the blood is an indication of essential fatty 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 15th and 16th 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.
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
Omega−3 fatty acids, also called Omega-3 oils, ω−3 fatty acids or ''n''−3 fatty acids, are polyunsaturated fatty acids (PUFAs) characterized by the presence of a double bond, three atoms away from the terminal methyl group in their chem ...
,
Eicosapentaenoic acid
Eicosapentaenoic acid (EPA; also icosapentaenoic acid) is an omega-3 fatty acid. In physiological literature, it is given the name 20:5(n-3). It also has the trivial name timnodonic acid. In chemical structure, EPA is a carboxylic acid with a 20-c ...
(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.
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
Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, ) that is responsible for formation of prostanoids, including thromboxane and prostaglandins such as pr ...
, or
cytochrome P450
Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
enzymes in serial metabolic pathways to metabolize EPA to
Resolvins
Resolvins are specialized pro-resolving mediators (SPMs) derived from omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as docosapentaenoic acid (DPA) and clupanodonic acid. As autacoids similar ...
of the E series (see
Specialized pro-resolving mediators#EPA-derived resolvins for further details on this metabolism) viz., resolvin E1 (RvE1) and RvE2.
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.
RvE1 and ReV2 are
specialized pro-resolving mediators
Specialized pro-resolving mediators (SPM, also termed specialized proresolving mediators) are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of ...
that contribute to the resolution of inflammation and other reactions.
Docosahexaenoic acid
ALOX5 acts in series with
ALOX15
ALOX15 (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically importa ...
to metabolize the omega 3 fatty acid,
docosahexaenoic acid
Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, and retina. In physiological literature, it is given the name 22:6(n-3). It can be synthesized from alpha-lino ...
(DHA, i.e. 4''Z'',7''Z'',10''Z'',13''Z'',16''Z'',19''Z''-docosahexaenoic acid), to D series resolvins (see
Specialized pro-resolving mediators#DHA-derived Resolvins for further details on this metabolism).
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
Specialized pro-resolving mediators (SPM, also termed specialized proresolving mediators) are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of ...
that contribute to the resolution of inflammation, promote tissue healing, and reduce the perception of inflammation-based pain (see
resolvin
Resolvins are specialized pro-resolving mediators (SPMs) derived from omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as docosapentaenoic acid (DPA) and clupanodonic acid. As autacoids similar ...
s).
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
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
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 and types of metabolites they form; the specific tissues responding to these agents; the times (e.g. early versus delayed) at which observations are made; and, very likely, various other factors.
''Alox5''
Gene knockout
A gene knockout (abbreviation: KO) is a genetic technique in which one of an organism's genes is made inoperative ("knocked out" of the organism). However, KO can also refer to the gene that is knocked out or the organism that carries the gene kno ...
mice are more susceptible to the development and pathological complications of experimental infection with ''
Klebsiella pneumoniae
''Klebsiella pneumoniae'' is a Gram-negative, non-motile, encapsulated, lactose- fermenting, facultative anaerobic, rod-shaped bacterium. It appears as a mucoid lactose fermenter on MacConkey agar.
Although found in the normal flora of the mo ...
'', ''
Borrelia burgdorferi
''Borrelia burgdorferi'' is a bacterial species of the spirochete class in the genus ''Borrelia'', and is one of the causative agents of Lyme disease in humans. Along with a few similar genospecies, some of which also cause Lyme disease, it make ...
'', and
Paracoccidioides brasiliensis
''Paracoccidioides brasiliensis'' is a dimorphic fungus and one of the two species that cause paracoccidioidomycosis (the other being ''Paracoccidioides lutzii).'' The fungus has been affiliated with the family Ajellomycetaceae (division Ascomyco ...
.
In a model of
cecum
The cecum or caecum is a pouch within the peritoneum that is considered to be the beginning of the large intestine. It is typically located on the right side of the body (the same side of the body as the appendix (anatomy), appendix, to which i ...
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
The peritoneum is the serous membrane forming the lining of the abdominal cavity or coelom in amniotes and some invertebrates, such as annelids. It covers most of the intra-abdominal (or coelomic) organs, and is composed of a layer of mesoth ...
. On the other hand, ALOX5 gene knockout mice demonstrate an enhanced resistance and lessened pathology to
Brucella abortus
''Brucella abortus'' is a Gram-negative bacterium in the family Brucellaceae and is one of the causative agents of brucellosis. The rod-shaped pathogen is classified under the domain Bacteria. The prokaryotic ''B. abortus'' is non-spore-forming, ...
infection
and, at least in its acute phase,
Trypanosoma cruzi
''Trypanosoma cruzi'' is a species of parasitic euglenoids. Among the protozoa, the trypanosomes characteristically bore tissue in another organism and feed on blood (primarily) and also lymph. This behaviour causes disease or the likelihood of ...
infection.
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
Respiratory syncytial virus (RSV), also called human respiratory syncytial virus (hRSV) and human orthopneumovirus, is a common, contagious virus that causes infections of the respiratory tract. It is a negative-sense, single-stranded RNA virus. ...
disease,
Lyme disease
Lyme disease, also known as Lyme borreliosis, is a vector-borne disease caused by the ''Borrelia'' bacterium, which is spread by ticks in the genus ''Ixodes''. The most common sign of infection is an expanding red rash, known as erythema migran ...
,
Toxoplasma gondii
''Toxoplasma gondii'' () is an obligate intracellular parasitic protozoan (specifically an apicomplexan) that causes toxoplasmosis. Found worldwide, ''T. gondii'' is capable of infecting virtually all warm-blooded animals, but felids, such as d ...
disease, and
corneal
The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Along with the anterior chamber and lens, the cornea refracts light, accounting for approximately two-thirds of the eye's total optical powe ...
injury. These studies indicate that Alox5 can serve a protective function presumably by generating metabolites such as chemotactic factors that mobilize the
innate immunity
The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...
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
Specialized pro-resolving mediators (SPM, also termed specialized proresolving mediators) are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of ...
(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.
''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
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are consider ...
s and CD8+ T
Cytotoxic T cell
A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pa ...
s to the sites of implantation.
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
The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...
by contributing to the mounting inflammatory responses to a wide range of acute (e.g.
pathogen
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
invasion, trauma, and burns
ee Inflammation#Causes); however, ALOX5 also contributes to the development and progression of excessive and chronic inflammatory responses such as rheumatoid arthritis,
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
, inflammatory bowel disease, and autoimmune diseases (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, 5''S''-HETE, which serve to attract and otherwise activate inflammation-inducing cells such as circulating leukocytes and tissue macrophages and
dendritic cells
Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. The ...
and b) lipoxin and resolvin subfamily of SPMs which tend to inhibit these cells as well as the overall inflammatory responses.
Allergy
ALOX5 contributes to the development and progression of
allergy
Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...
and
allergic inflammation reactions and diseases such as allergic
rhinitis
Rhinitis, also known as coryza, is irritation and inflammation of the mucous membrane inside the nose. Common symptoms are a stuffy nose, runny nose, sneezing, and post-nasal drip.
The inflammation is caused by viruses, bacteria, irritants o ...
,
conjunctivitis
Conjunctivitis, also known as pink eye, is inflammation of the conjunctiva, outermost layer of the white part of the eye and the inner surface of the eyelid. It makes the eye appear pink or reddish. Pain, burning, scratchiness, or itchiness may ...
,
asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...
,
rash
A rash is a change of the human skin which affects its color, appearance, or texture.
A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cr ...
es, and
eczema
Dermatitis is inflammation of the Human skin, skin, typically characterized by itchiness, erythema, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become lichenification, thick ...
(see
Alergy#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
Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...
.
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.
Hypersensitivity reactions
ALOX5 contributes to non-allergic reactions of the
respiratory system
The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animals and plants. The anatomy and physiology that make this happen varies grea ...
and skin such as
aspirin-induced asthma
Aspirin exacerbated respiratory disease (AERD), also termed aspirin-induced asthma, is a medical condition initially defined as consisting of three key features: asthma, respiratory symptoms exacerbated by aspirin and other nonsteroidal anti-inf ...
,
NSAID hypersensitivity reactions, NSAID-induced
nonallergic rhinitis
Nonallergic rhinitis is rhinitis—inflammation of the inner part of the nose—not caused by an allergy. Nonallergic rhinitis displays symptoms including chronic sneezing or having a congested, drippy nose, without an identified allergic reaction ...
, NSAID-induced non-allergic
conjunctivitis
Conjunctivitis, also known as pink eye, is inflammation of the conjunctiva, outermost layer of the white part of the eye and the inner surface of the eyelid. It makes the eye appear pink or reddish. Pain, burning, scratchiness, or itchiness may ...
, NSAID-induced
angioedema
Angioedema is an area of swelling ( edema) of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which ...
, or NSAID-induced
urticarial
Hives, also known as urticaria, is a kind of skin rash with red, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and does not leave any long-lasti ...
; 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.
ALOX5-inhibiting drugs
The tissue, animal model, and animal and human genetic studies cited above implicate ALOX5 in a wide range of diseases: a) excessive inflammatory responses to
pathogen
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
s, trauma, burns, and other forms of tissue injury
ee_Inflammation#Causes);_b)_chronic_inflammatory_conditions_such_as_rheumatoid_arthritis.html" ;"title="Inflammation#Causes.html" ;"title="ee Inflammation#Causes">ee Inflammation#Causes); b) chronic inflammatory conditions such as rheumatoid arthritis">Inflammation#Causes.html" ;"title="ee Inflammation#Causes">ee Inflammation#Causes); b) chronic inflammatory conditions such as rheumatoid arthritis,
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
, inflammatory bowel disease, autoimmune diseases, and Alzheimer's disease (see Inflammation#Disorders); c)
allergy
Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...
and
allergic inflammation reactions such as allergic
rhinitis
Rhinitis, also known as coryza, is irritation and inflammation of the mucous membrane inside the nose. Common symptoms are a stuffy nose, runny nose, sneezing, and post-nasal drip.
The inflammation is caused by viruses, bacteria, irritants o ...
,
conjunctivitis
Conjunctivitis, also known as pink eye, is inflammation of the conjunctiva, outermost layer of the white part of the eye and the inner surface of the eyelid. It makes the eye appear pink or reddish. Pain, burning, scratchiness, or itchiness may ...
,
asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...
,
rash
A rash is a change of the human skin which affects its color, appearance, or texture.
A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cr ...
es, and
eczema
Dermatitis is inflammation of the Human skin, skin, typically characterized by itchiness, erythema, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become lichenification, thick ...
; d) NSAID-induced acute non-allergic reactions such as asthma, rhinitis, conjunctivitis,
angioedema
Angioedema is an area of swelling ( edema) of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which ...
and
urticaria
Hives, also known as urticaria, is a kind of skin rash with red, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and does not leave any long-lasti ...
; and e) 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
Zileuton (trade name Zyflo) is an orally active inhibitor of 5-lipoxygenase, and thus inhibits leukotrienes (LTB4, LTC4, LTD4, and LTE4) formation, used for the maintenance treatment of asthma. Zileuton was introduced in 1996 by Abbott Laborat ...
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.
Zileuton is currently undergoing a phase II study for the treatment of
acne vulgaris
Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and po ...
(mild-to-moderate inflammatory facial acne) and a phase I study (see
Clinical trial#phases) combining it with
imatinib
Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral chemotherapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple receptor tyrosine kin ...
for treating
chronic myeloid leukemia
Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulati ...
.
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).
Given these deficiencies, other drugs targeting ALOX5 are under study.
Flavocoxid is a proprietary blend of purified plant derived bioflavonoids including
Baicalin
As baicalin is a flavone glycoside, it is a flavonoid. It is the glucuronide of baicalein.
Natural occurrences
Baicalin is found in several species in the genus ''Scutellaria'', including ''Scutellaria baicalensis'', and '' Scutellaria lateri ...
and
Catechin
Catechin is a flavan-3-ol, a type of secondary metabolite providing antioxidant roles in plants. It belongs to the subgroup of polyphenols called flavonoids.
The name of the catechin chemical family derives from ''catechu'', which is the tannic ...
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 mg under the commercial name Limbrel. However, in
clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
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.
Setileuton (MK-0633) has completed a Phase II clinical trial for the treatment of asthma,
chronic obstructive lung disease
Chronic obstructive pulmonary disease (COPD) is a type of progressive Obstructive lung disease, lung disease characterized by long-term respiratory symptoms and airflow limitation. The main symptoms include shortness of breath and a cough, which ...
, and atherosclerosis (NCT00404313, NCT00418613, and NCT00421278, respectively).
PF-4191834 has completed phase II studies for the treatment of asthma (NCT00723021).
Hyperforin
Hyperforin is a phytochemical produced by some of the members of the plant genus '' Hypericum'', notably '' Hypericum perforatum'' (St John's wort). Hyperforin may be involved in the pharmacological effects of St. John's wort, specifically in its ...
, an active constituent of the herb
St John's wort
''Hypericum perforatum'', known as St. John's wort, is a flowering plant in the family Hypericaceae and the type species of the genus ''Hypericum''.
Possibly a hybrid between '' H. maculatum'' and '' H. attenuatum'', the species can be found a ...
, is active at micro
molar concentration
Molar concentration (also called molarity, amount concentration or substance concentration) is a measure of the concentration of a chemical species, in particular of a solute in a solution, in terms of amount of substance per unit volume of solut ...
s in inhibiting ALOX5.
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.
In addition,
curcumin
Curcumin is a bright yellow chemical produced by plants of the ''Curcuma longa'' species. It is the principal curcuminoid of turmeric (''Curcuma longa''), a member of the ginger family, Zingiberaceae. It is sold as a herbal supplement, cosmetic ...
, a constituent of
turmeric
Turmeric () is a flowering plant, ''Curcuma longa'' (), of the ginger family, Zingiberaceae, the rhizomes of which are used in cooking. The plant is a perennial, rhizomatous, herbaceous plant native to the Indian subcontinent and Southeast Asi ...
, is a 5-LO inhibitor as defined by
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
studies of the enzyme.
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.
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
Montelukast, sold under the brand name Singulair among others, is a medication used in the maintenance treatment of asthma. It is generally less preferred for this use than inhaled corticosteroids. It is not useful for acute asthma attacks. Ot ...
,
Zafirlukast
Zafirlukast is an orally administered leukotriene receptor antagonist (LTRA) used for the chronic treatment of asthma. While zafirlukast is generally well tolerated, headache and stomach upset often occur. Some rare side effects can occur, which ...
, and
Pranlukast
Pranlukast (brand name Onon, オノン) is a cysteinyl leukotriene receptor-1 antagonist. This drug works similarly to Merck & Co.'s montelukast (Singulair). It is widely used in Japan.
Medications of this class, which go under a variety of nam ...
are
receptor antagonists
A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of recep ...
for the
Cysteinyl leukotriene receptor 1
Cysteinyl leukotriene receptor 1, also termed CYSLTR1, is a receptor for cysteinyl leukotrienes (LT) (see leukotrienes#Cysteinyl leukotrienes). CYSLTR1, by binding these cysteinyl LTs (CysLTs; viz, LTC4, LTD4, and to a much lesser extent, LTE4) c ...
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
and also may be useful for treating acquired childhood
sleep apnea
Sleep apnea, also spelled sleep apnoea, is a sleep disorder in which pauses in breathing or periods of shallow breathing during sleep occur more often than normal. Each pause can last for a few seconds to a few minutes and they happen many times ...
due to adenotonsillar hypertrophy (see
Acquired non-inflammatory myopathy#Diet and Trauma Induced Myopathy).
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
A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of rece ...
s have proven inferior to
corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...
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
Beta2-adrenergic agonists, also known as adrenergic β2 receptor agonists, are a class of drugs that act on the β2 adrenergic receptor. Like other β adrenergic agonists, they cause smooth muscle relaxation. β2 adrenergic agonists' effect ...
drugs in the treatment of asthma.
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 in the human ''ALOX5'' gene commonly possess five GGGCCGG repeats which bind the
Sp1 transcription factor
Transcription factor Sp1, also known as specificity protein 1* is a protein that in humans is encoded by the SP1 gene.
Function
The protein encoded by this gene is a zinc finger transcription factor that binds to GC-rich motifs of many promote ...
and thereby increase the gene's transcription of ALOX5.
Homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
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
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...
. These variants are associated with reduced levels of ALOX5 as well as reduced production of LTC4 in their eosinophils.
These data suggest that ALOX5 may contribute to dampening the severity of asthma, possibly by metabolizing PUFA to
specialized pro-resolving mediators
Specialized pro-resolving mediators (SPM, also termed specialized proresolving mediators) are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of ...
.
Single nucleotide polymorphism
In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...
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
Leukotriene A4 hydrolase, also known as LTA4H is a human gene. The protein encoded by this gene is a bifunctional enzyme () which converts leukotriene A4 to leukotriene B4 and acts as an aminopeptidase.
Function
This enzyme belongs to the family ...
), or are the cellular receptors responsible for mediating the cellular responses to the down-stream ALOX products LTC4 and LTD4 (i.e.
CYSLTR1
Cysteinyl leukotriene receptor 1, also termed CYSLTR1, is a receptor for cysteinyl leukotrienes (LT) (see leukotrienes#Cysteinyl leukotrienes). CYSLTR1, by binding these cysteinyl LTs (CysLTs; viz, LTC4, LTD4, and to a much lesser extent, LTE4) c ...
and
CYSLTR2
Cysteinyl leukotriene receptor 2, also termed CYSLTR2, is a receptor for cysteinyl leukotrienes (LT) (see leukotrienes#Cysteinyl leukotrienes). CYSLTR2, by binding these cysteinyl LTs (CysLTs; viz, LTC4, LTD4, and to a much lesser extent, LT ...
) 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.
NSAID-induced non-allergic reactions
Aspirin
Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...
and other
non-steroidal anti-inflammatory drug
Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...
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
Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing disc ...
, and/or
nasal congestion
Nasal congestion is the blockage of nasal breathing usually due to membranes lining the nose becoming swollen from inflamed blood vessels.
Background
In about 85% of cases, nasal congestion leads to mouth breathing rather than nasal breathing. ...
/
rhinorrhea
Rhinorrhea, rhinorrhoea, or informally runny nose is the free discharge of a thin mucus fluid from the nose; it is a common condition. It is a common symptom of allergies ( hay fever) or certain viral infections, such as the common cold or COVID- ...
occurring shortly after NSAID ingestion in patients with a history of
asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...
and/or
rhinosinusitis
Rhinosinusitis is a simultaneous infection of the nasal mucosa (rhinitis) and an infection of the mucosa of the paranasal sinuses ( sinusitis). A distinction is made between acute rhinosinusitis and chronic rhinosinusitis.
Background
Because sin ...
; 2) NSAIDs-exacerbated cutaneous disease (NECD), i.e.
wheal response
A skin condition, also known as cutaneous condition, is any medical condition that affects the integumentary system—the organ system that encloses the body and includes skin, nails, and related muscle and glands. The major function of this ...
s and/or
angioedema
Angioedema is an area of swelling ( edema) of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which ...
responses occurring shortly after NSAID ingestion in patients with a history of
chronic urticaria
Hives, also known as urticaria, is a kind of skin rash with red, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and does not leave any long-lasti ...
; 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
Hives, also known as urticaria, is a kind of skin rash with red, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and does not leave any long-lasti ...
).
The
genetic polymorphism
A gene is said to be polymorphic if more than one allele occupies that gene's locus within a population. In addition to having more than one allele at a specific locus, each allele must also occur in the population at a rate of at least 1% to gen ...
Single-nucleotide polymorphism
In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently lar ...
(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, rs1565096, and rs7894352,
are associated with NSAID-induced cutaneous reactions in Spanish patients.
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
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
, 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.
See also
Arachidonate 5-lipoxygenase inhibitor Arachidonate 5-lipoxygenase inhibitors are compounds that slow or stop the action of the arachidonate 5-lipoxygenase (5-lipoxygenase or 5-LOX) enzyme, which is responsible for the production of inflammatory leukotrienes. The overproduction of leukot ...
References
Further reading
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
External links
*
*
{{Portal bar, Biology, border=no
EC 1.13.11
Enzymes
Eicosanoids
Peripheral membrane proteins