15-LOX-1
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ALOX15 (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other
lipoxygenase Lipoxygenases () (LOX) are a family of (non- heme) iron-containing enzymes, more specifically oxidative enzymes, most of which catalyze the dioxygenation of polyunsaturated fatty acids in lipids containing a cis,cis-1,4- pentadiene into ce ...
s, a seminal
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
in the metabolism of
polyunsaturated fatty acid In biochemistry and nutrition, a polyunsaturated fat is a fat that contains a polyunsaturated fatty acid (abbreviated PUFA), which is a subclass of fatty acid characterized by a backbone with two or more carbon–carbon double bonds. Some polyunsa ...
s to a wide range of physiologically and pathologically important products. ▼ Gene Function Kelavkar and Badr (1999) stated that the ALOX15 gene product is implicated in antiinflammation, membrane remodeling, and cancer development/metastasis. Kelavkar and Badr (1999) described experiments yielding data that supported the hypothesis that loss of the TP53 gene, or gain-of-function activities resulting from the expression of its mutant forms, regulates ALOX15 promoter activity in human and in mouse, albeit in directionally opposite manners. These studies defined a direct link between ALOX15 gene activity and an established tumor-suppressor gene located in close chromosomal proximity. Kelavkar and Badr (1999) referred to this as evidence that 15-lipoxygenase is a mutator gene. ▼ Mapping By PCR analysis of a human-hamster somatic hybrid DNA panel, Funk et al. (1992) demonstrated that genes for 12-lipoxygenase and 15-lipoxygenase are located on human chromosome 17, whereas the most unrelated lipoxygenase (5-lipoxygenase) was mapped to chromosome 10. Kelavkar and Badr (1999) stated that the ALOX15 gene maps to 17p13.3 in close proximity to the tumor-suppressor gene TP53 (191170). In humans, it is encoded by the ALOX15
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
located on
chromosome 17 Chromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more than 84 million base pairs (the building material of DNA) and represents between 2.5 and 3% of the total DN ...
p13.3. This 11 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 ...
gene consists of 14
exon 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 ...
s and 13
intron 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., gen ...
s coding for a 75
kilodalton The dalton or unified atomic mass unit (symbols: Da or u, respectively) is a unit of mass defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at rest. It is a non-SI unit accepted f ...
protein composed of 662 amino acids. 15-LO is to be distinguished from another human 15-lipoxygenase enzyme,
ALOX15B Arachidonate 15-lipoxygenase type II is an enzyme that in humans is encoded by the ''ALOX15B'' gene. ALOX15B, also known as 15-lipoxygenase-2 (15-LO-2 or 15-LOX-2), is distinguished from its related oxygenase, ALOX15 or 15-lipoxygenase-1. Funct ...
(also termed 15-lipoxygenase-2).
Orthologs Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...
of ALOX15, termed Alox15, are widely distributed in animal and plant species but commonly have different enzyme activities and make somewhat different products than ALOX15.


Nomenclature

Human ALOX15 was initially named arachidonate 15-lipoxygenase or 15-lipoxygenase, but subsequent studies uncovered a second human enzyme with 15-lipoxygenase activity as well as various non-human mammalian Alox15 enzymes that are closely related to and therefore
orthologs Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...
of human ALOX15. Many of the latter Alox15 enzymes nonetheless possess predominantly or exclusively
12-lipoxygenase ALOX12 (), also known as arachidonate 12-lipoxygenase, 12-lipoxygenase, 12''S''-Lipoxygenase, 12-LOX, and 12''S''-LOX is a lipoxygenase-type enzyme that in humans is encoded by the ''ALOX12'' gene which is located along with other lipoyxgenases on ...
rather than 15-lipoxygenase activity. Consequently, human ALOX15 is now referred to as arachidonate-15-lipoxygenase-1, 15-lipoxygenase-1, 15-LOX-1, 15-LO-1, human 12/15-lipoxygenase, leukocyte-type arachidonate 12-lipoxygenase, or arachidonate omega–6 lipoxygenase. The second discovered human 15-lipoxygenase, a product of the
ALOX15B Arachidonate 15-lipoxygenase type II is an enzyme that in humans is encoded by the ''ALOX15B'' gene. ALOX15B, also known as 15-lipoxygenase-2 (15-LO-2 or 15-LOX-2), is distinguished from its related oxygenase, ALOX15 or 15-lipoxygenase-1. Funct ...
gene, is termed ALOX15B, arachidonate 15-lipoxygenase 2, 15-lipoxygenase-2, 15-LOX-2, 15-LO-2, arachidonate 15-lipoxygenase type II, arachidonate 15-lipoxygenase, second type, and arachidonate 15-lipoxygenase; and mouse, rat, and rabbit rodent orthologs of human ALOX15, which share 74-81% amino acid identity with the human enzyme, are commonly termed Alox15, 12/15-lipoxygenase, 12/15-LOX, or 12/15-LO). Both human ALOX15 and ALOX15B genes are located on chromosome 17; their product proteins have an amino acid sequence identity of only ~38%; they also differ in the
polyunsaturated fatty acid In biochemistry and nutrition, a polyunsaturated fat is a fat that contains a polyunsaturated fatty acid (abbreviated PUFA), which is a subclass of fatty acid characterized by a backbone with two or more carbon–carbon double bonds. Some polyunsa ...
s that they prefer as substrates and exhibit different product profiles when acting on the same substrates.


Tissue distribution

Human ALOX15 protein is highly expressed in circulating blood
eosinophil Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along wi ...
s and
reticulocyte In hematology, reticulocytes are immature red blood cells (RBCs). In the process of erythropoiesis (red blood cell formation), reticulocytes develop and mature in the bone marrow and then circulate for about a day in the blood stream before dev ...
s, cells, bronchial airway epithelial cells, mammary epithelial cells, the
Reed–Sternberg cell Reed–Sternberg cells (also known as lacunar histiocytes for certain types) are distinctive, giant cells found with light microscopy in biopsies from individuals with Hodgkin lymphoma. They are usually derived from B lymphocytes, classicall ...
s of
Hodgkin's lymphoma Hodgkin lymphoma (HL) is a type of lymphoma in which cancer originates from a specific type of white blood cell called lymphocytes, where multinucleated Reed–Sternberg cells (RS cells) are present in the lymph nodes. The condition was named a ...
,
cornea The cornea is the transparency (optics), transparent front part of the eyeball which covers the Iris (anatomy), iris, pupil, and Anterior chamber of eyeball, anterior chamber. Along with the anterior chamber and Lens (anatomy), lens, the cornea ...
l epithelial cells, and
dendritic cell A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...
s; it is less strongly expressed in alveolar
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s, tissue
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 p ...
s, tissue
fibroblast A fibroblast is a type of cell (biology), biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and ...
s, circulating blood
neutrophil Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in differe ...
s, vascular
endothelial cells The endothelium (: endothelia) 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 res ...
, joint
synovial membrane Synovial () may refer to: * Synovial fluid * Synovial joint A synovial joint, also known as diarthrosis, joins bones or cartilage with a fibrous joint capsule that is continuous with the periosteum of the joined bones, constitutes the outer bou ...
cells,
seminal fluid Semen, also known as seminal fluid, is a bodily fluid that contains spermatozoa which is secreted by the male gonads (sexual glands) and other sexual organs of male or hermaphroditic animals. In humans and placental mammals, seminal fluid i ...
, prostate epithelium cells, and mammary ductal epithelial cells. The distribution of Alox15 in sub-human primates and, in particular, rodents differs significantly from that of human ALOX15; this, along with their different principal product formation (e.g. 12-HETE rather than 15-HETE) has made the findings of Alox15 functions in rat, mouse, or rabbit models difficult to extrapolate to the function of ALOX15 in humans.


Enzyme activities


Lipoxygenase activity

ALOX15 and Alox15 enzymes are non-heme, iron-containing
dioxygenase Dioxygenases are oxidoreductase enzymes. Aerobic organism, 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 energ ...
s. They commonly catalyze the attachment of molecular oxygen as a
peroxy In chemistry, peroxides are a group of compounds with the structure , where the R's represent a radical (a portion of a complete molecule; not necessarily a free radical) and O's are single oxygen atoms. Oxygen atoms are joined to each other and ...
residue to
polyunsaturated fatty acids In biochemistry and nutrition, a polyunsaturated fat is a fat that contains a polyunsaturated fatty acid (abbreviated PUFA), which is a subclass of fatty acid characterized by a backbone with two or more carbon–carbon double bonds. Some polyunsa ...
(PUFA) that contain two carbon–carbon
double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
s that for the human ALOX15 are located between carbons 10 and 9 and 7 and 6 as numbered counting backward from the last or omega (i.e. ω) carbon at the methyl end of the PUFA (these carbons are also termed ω–10 and ω–9 and ω–7 and ω–6). In PUFAs that do not have a third carbon–carbon double bond between their ω–13 and ω–12 carbons, human ALOX15 forms ω–6 peroxy intermediates; in PUFAs that do have this third double bond, human ALOX15 makes the ω–6 peroxy intermediate but also small amounts of the ω–9 peroxy intermediate. Rodent Alox15 enzymes, in contrast, produce almost exclusively ω–9 peroxy intermediates. Concurrently, ALOX15 and rodent Alox15 enzymes rearrange the carbon–carbon double bonds to bring them into the 1''S''-hydroxy-2''E'',4''Z''-
diene In organic chemistry, a diene ( ); also diolefin, ) or alkadiene) is a covalent compound that contains two double bonds, usually among carbon atoms. They thus contain two alk''ene'' units, with the standard prefix ''di'' of systematic nome ...
configuration. ALOX15 and Alox15 enzymes act with a high degree of
stereospecificity In chemistry, stereospecificity is the property of a reaction mechanism that leads to different stereoisomeric reaction products from different stereoisomeric reactants, or which operates on only one (or a subset) of the stereoisomers."Overlap C ...
to form products that position the hydroperoxy residue in the ''S''
stereoisomer In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in ...
configuration.


Lipohydroperoxidase activity

Human ALOX15 can also convert the peroxy PUFA intermediate to a cyclic ether with a three-atom ring, i.e. an
epoxide In organic chemistry, an epoxide is a cyclic ether, where the ether forms a three-atom ring: two atoms of carbon and one atom of oxygen. This triangular structure has substantial ring strain, making epoxides highly reactive, more so than other ...
intermediate that is attacked by a water molecule to form epoxy-hydroxy PUFA products. Eoxins stimulate vascular permeability in an ''ex vivo'' human vascular endothelial model system.


Leukotriene synthase activity

The PUFA epoxide of arachidonic acid made by ALOX15 - eoxin A4 may also be conjugated with glutathione to form eoxin B4 which product can be further metabolized to eoxin C4, and eoxin D4.


Substrates, substrate metabolites, and metabolite activities

Among their physiological substrates, human and rodent ALOX15 enzymes act on
linoleic acid Linoleic acid (LA) is an organic compound with the formula . Both alkene groups () are ''cis''. It is a fatty acid sometimes denoted 18:2 (n−6) or 18:2 ''cis''-9,12. A linoleate is a salt or ester of this acid. Linoleic acid is a polyunsat ...
, alpha-linolenic acid, gamma-linolenic acid, arachidonic acid,
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 wi ...
, and
docosahexaenoic acid Docosahexaenoic acid (DHA) is an omega−3 fatty acid that is an important component of the human brain, cerebral cortex, skin, and retina. It is given the fatty acid notation 22:6(''n''−3). It can be synthesized from alpha-linolenic acid or ...
when presented not only as free acids but also when incorporated as
ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...
s in
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 ...
s,
glyceride Glycerides, also known as acylglycerols, are esters formed from glycerol and fatty acids, and are generally very hydrophobic. Glycerol has three hydroxyl functional groups, which can be esterified with one, two, or three fatty acids to form mo ...
s, or
cholesteryl ester 300px, Cholesteryl oleate, a member of the cholesteryl ester family Cholesteryl esters are a type of dietary lipid and are ester derivatives of cholesterol. The ester bond is formed between the carboxylate group of a fatty acid and the hydroxyl g ...
s. The human enzyme is particularly active on linoleic acid, preferring it over arachidonic acid. It is less active on PUFA that are esters within the cited lipids.


Arachidonic acid

Arachidonic acid (AA) has
double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
s between carbons 5-6, 8-9, 11-12, and 14-15; these double bonds are in a ''cis'' or ''Z'' configuration rather than a ''trans'' or ''E'' configuration. ALOX15 adds a hydroperoxy residue to AA at carbons 15 and to a lesser extent 12 to form 15(''S'')-hydroperoxy-5''Z'',8''Z'',11''Z'',13''E''-eicosatetraenoic acid (15(''S'')-HpETE) and 12(''S'')-hydroperoxy-5''Z'',8''Z'',10''E'',14Z-eicosatetraenoic acid (12(''S'')-HpETE); the purified enzyme makes 15(''S'')-HpETE and 12(''S'')-HpETE in a product ratio of ~4-9 to 1. Both products may be rapidly reduced by 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 ...
enzymes to their corresponding hydroxy analogs, 15(''S'')-HETE and 12(''S'')-HETE. 15(''S'')-HpETE and 15(''S'')-HETE bind to and activate the
leukotriene B4 receptor 2 Leukotriene B4 receptor 2, also known as BLT2, BLT2 receptor, and BLTR2, is an Integral membrane protein that is encoded by the LTB4R2 gene in humans and the Ltbr2 gene in mice. Discovered several years after the leukotriene B4 receptor 1 (BLT ...
, activate the
peroxisome proliferator-activated receptor gamma Peroxisome proliferator-activated receptor gamma (PPAR-γ or PPARG), also known as the glitazone reverse insulin resistance receptor, or NR1C3 (nuclear receptor subfamily 1, group C, member 3) is a type II nuclear receptor functioning as a transc ...
, and at high concentrations cause cells to generate toxic
reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
; one or more of these effects may be at least in part responsible for their ability to promote inflammatory responses, alter the growth of various times of human cancer cell lines, contract various types of blood vessels, and stimulate pathological fibrosis in pulmonary arteries and liver (see ). 15(''S'')-HpETE and 15(''S'')-HETE are esterified into membrane
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 ...
s where they may be stored and subsequently released during cell stimulation. As one aspect of this processing, the two products are progressively esterified in
mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...
membrane phospholipids during the maturation of
red blood cell Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...
s and thereby may serve to signal for the degradation of the mitochondria and the maturation of these precursors to red blood cells in mice. This pathway operates along with two other mitochondria-removing pathways and therefore does not appear essential for mouse red blood cell maturation. 15-(''S'')-HpETE and 15(''S'')-HETE may be further metabolized to various bioactive products including: *
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-resolvi ...
(LX)A4, LXB4, AT-LXA4, and AT-LXB4; these metabolites are members of the
specialized pro-resolving mediator Specialization or Specialized may refer to: Academia * Academic specialization, may be a course of study or major at an academic institution or may refer to the field in which a specialist practices * Specialty (medicine), a branch of medical ...
class of anti-inflammatory agents that contribute to the resolution of inflammatory responses and inflammation-based diseases in animal models and, potentially, humans. *
Hepoxilin Hepoxilins (Hx) are a set of epoxyalcohol metabolites of polyunsaturated fatty acids (PUFA), i.e. they possess both an epoxide and an alcohol (i.e. hydroxyl) residue. HxA3, HxB3, and their non-enzymatically formed isomers are nonclassic eicosanoi ...
isomers (e.g. 11''S''-hydroxy-14''S'',15''S''-epoxy-5''Z'',8''Z'',12''E''-eicosatrienoic acid (14,15-HxA3) and 13''R''-hydroxy-14''S'',15''S''-epoxy-5''Z'',8''Z'',11''Z''-eicosatrienoic acid (14,15-HxB3)) which may contribute to the regulation of inflammation responses and
insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
secretion. *
Eoxin Eoxins are proposed to be a family of proinflammatory eicosanoids (signaling compounds that regulate inflammatory and immune responses). They are produced by human eosinophils (a class of white blood cells), mast cells, the L1236 Reed–Sternberg ...
s (e.g. eoxin C4, 14,15-eoxin D4, and eoxin E4) which have pro-inflammatory actions and contribute to severe
asthma Asthma is a common 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 wh ...
,
aspirin-exacerbated respiratory disease Aspirin-exacerbated respiratory disease (AERD), also called NSAID-exacerbated respiratory disease (N-ERD) or historically aspirin-induced asthma and Samter's Triad, is a long-term disease defined by three simultaneous symptoms: asthma, chronic ...
attacks, and other
allergy Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include Allergic rhinitis, hay fever, Food allergy, food al ...
reactions; they may also be involved in the pathology of
Hodgkins disease Hodgkin lymphoma (HL) is a type of lymphoma in which cancer originates from a specific type of white blood cell called lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocyte ...
. *
Poxytrin Poxytrins or dihydroxy-''E'',''Z'',''E''-polyunsaturated fatty acids (dihydroxy-''E'',''Z'',''E''-PUFAs) are PUFA metabolites that possess two hydroxyl residues and three in-series conjugated double bonds in an ''E'',''Z'',''E'' cis–trans confi ...
8(''S''),15(''S'')-dihydroxy-5''Z'',9''E'',11''Z'',13''E''-eicosatetraenoic acid (8(''S''),15(''S'')-diHETE), an inhibitor of human platelet aggregation. * 5(''S''),15(''S'')-Dihydroxy-6''Z'',8''E'',11''E'',13''Z''-eicosatetraenoic acid (5(''S''),15(''S'')-diHETE) and its 5-
ketone In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...
analog, 5-oxo-15(''S'')-hydroxy-ETE. These are weak and potent, respectively, stimulators of human
eosinophil Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along wi ...
,
neutrophil Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in differe ...
, and
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 monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
chemotaxis Chemotaxis (from ''chemical substance, chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell organism, single-cell or multicellular organisms direct thei ...
and thereby possible contributors to human allergic and non-allergic
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
responses (see ). * 15-Oxo-ETE which inhibits the growth of cultured
human umbilical vein endothelial cell Human umbilical vein endothelial cells (HUVECs) are cells derived from the endothelium of veins from the umbilical cord. They are used as a laboratory model system for the study of the function and pathology of endothelial cells (e.g., angiogenesi ...
s and various human cancer cell lines; it is also has activities on
THP1 cell line THP-1 is a human monocytic cell line derived from an acute monocytic leukemia patient. It is used to test leukemia cell lines in immunocytochemical analysis of protein-protein interactions, and immunohistochemistry. Characteristics Although ...
cells suggesting that it might act as an inhibitor of inflammatory and
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
reactions (see ). The minor products of ALOX15, 12-(''S'')-HpETE and 12(''S'')-HETE, possess a broad range of activities. One or both of these compounds stimulates cells by binding with and activating two
G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...
s, GPR31 and the
leukotriene B4 receptor 2 Leukotriene B4 receptor 2, also known as BLT2, BLT2 receptor, and BLTR2, is an Integral membrane protein that is encoded by the LTB4R2 gene in humans and the Ltbr2 gene in mice. Discovered several years after the leukotriene B4 receptor 1 (BLT ...
; 12(''S'')-HETE also acts as a
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 rec ...
by binding to but not stimulating the
thromboxane receptor The thromboxane receptor (TP) also known as the prostanoid TP receptor is a protein that in humans is encoded by the ''TBXA2R'' gene, The thromboxane receptor is one among the five classes of prostaglandin receptor, prostanoid receptors and was ...
thereby inhibiting the actions of
thromboxane A2 Thromboxane A2 (TXA2) is a type of thromboxane that is produced by activated platelets during hemostasis and has prothrombotic properties: it stimulates activation of new platelets as well as increases platelet aggregation. This is achieved by a ...
and
prostaglandin H2 Prostaglandin H2 (PGH2), or prostaglandin H2 (PGH2), is a type of prostaglandin and a precursor for many other biologically significant molecules. It is synthesized from arachidonic acid in a reaction catalyzed by a cyclooxygenase enzyme. The con ...
(see ). As at least a partial consequence of these receptor-directed actions, one or both the two ALOX15 products exhibit pro-inflammation, diabetes-inducing, and vasodilation activities in animal models; cancer-promoting activity on cultured human cancer cells; and other actions (see ). The two products are also further metabolized to various bioactive products including: * Hepoxilin A3 and Hepoxilin B3 along with their respective tri-hydroxyl metabolites, trioxilin A3 and trioxilin B3. These metabolites have been reported to have anti-inflammatory activity, to have
vasodilation Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel wa ...
activity, to promote pain perception, to reverse oxidative stress in cells, and to promote insulin secretion in animal model systems (see
Hepoxilin Hepoxilins (Hx) are a set of epoxyalcohol metabolites of polyunsaturated fatty acids (PUFA), i.e. they possess both an epoxide and an alcohol (i.e. hydroxyl) residue. HxA3, HxB3, and their non-enzymatically formed isomers are nonclassic eicosanoi ...
). * 12-Oxo-ETE, which along with 12(''S'')-HETE, activates the
leukotriene B4 Leukotriene B4 (LTB4) is a leukotriene involved in inflammation. It has been shown to promote insulin resistance in obese mice. Biochemistry LTB4 is a leukotriene involved in inflammation. It is produced from leukocytes in response to inflammato ...
receptor,
leukotriene B4 receptor 2 Leukotriene B4 receptor 2, also known as BLT2, BLT2 receptor, and BLTR2, is an Integral membrane protein that is encoded by the LTB4R2 gene in humans and the Ltbr2 gene in mice. Discovered several years after the leukotriene B4 receptor 1 (BLT ...
(BLT2) but not its
leukotriene B4 receptor The leukotriene B4 receptors (BLTRs) include the following two receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (bio ...
1 (BLT1). This allows the possibility that 12-oxo-ETE contributes to the pro-inflammatory and other activities that BLT2 regulates (see and
Leukotriene B4 receptor 2 Leukotriene B4 receptor 2, also known as BLT2, BLT2 receptor, and BLTR2, is an Integral membrane protein that is encoded by the LTB4R2 gene in humans and the Ltbr2 gene in mice. Discovered several years after the leukotriene B4 receptor 1 (BLT ...
).


Docosahexaenoic acid

Human ALOX15 metabolizes docosahexaenoic acid (DHA) to 17''S''-Hydroperoxy-4''Z'',7''Z'',10''Z'',13''Z'',15''E'',19''Z''-docosahexaenoic acid (17''S''-HpDHA) and 17''S''-hydroxy-4''Z'',7''Z'',10''Z'',13''Z'',15''E'',19''Z''-docosahexaenoic acid (17''S''-HDHA). One or both of these products stimulate human breast and prostate cell lines to proliferate in culture and 17''S''-HDHA possesses potent specialized proresolving mediator activity (see ). One or both of these products may be further metabolized enzymatically to: *
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 from two isomers of docosapentaenoic acid (DPA), one omega-3 and one ...
Ds (RvDs), i.e. RvD-1, RvD2, RvD3, RvD4, RvD5, RvD6, and protectin Ds (PDs), i.e. PD1, PDX, 20-hydroxy-PD1, 17-epi-PD1, and 10-epi-PD1 (see Neuroprotectin D1 and ). These products are members of, and have a wide range of activities common to, the
specialized proresolving mediators Specialization or Specialized may refer to: Academia * Academic specialization, may be a course of study or major at an academic institution or may refer to the field in which a specialist practices * Specialty (medicine), a branch of medical ...
class of metabolites.


Eicosapentaenoic acid

Human ALOX15 metabolizes eicosapentaenoic acid to 15''S''-hydroperoxy-5''Z'',8''Z'',11''Z'',13''E'',17''E''-eicosapentaenoic acid (15''S''-HpEPA) and 15''S''-hydroxy-5''Z'',8''Z'',11''Z'',13''E'',17''E''-eicosapentaenoic acid (15''S''-HEPA); 15''S''-HEPA inhibits
ALOX5 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. Arachidonate 5-lipoxygenase is a member of the lipoxygenase fa ...
-dependent production of the pro-inflammatory mediator, LTB4, in cells, and may thereby serve an anti-inflammatory function. These products may be further metabolized to: * Resolvin E3, a specialized proresolvin mediator with anti-inflammatory activity (see i.e. RvE).


n-3 Docosapentaenoic acid

Human cells and mouse tissues metabolize n-3 docosapentaenoic acid (i.e., 7''Z'',10''Z'',13''Z'',16''Z'',19''Z''-docosapentaenoic acid, or
clupanodonic acid Docosapentaenoic acid (DPA) designates any straight open chain polyunsaturated fatty acid (PUFA) which contains 22 carbons and 5 double bonds. DPA is primarily used to designate two isomers, ''all''-''cis''-4,7,10,13,16-docosapentaenoic acid (i.e. ...
) to a series of products that have been classified as specialized proresolvin mediators. Base on the analogy to docosahexaenoic acid metabolism to resolving D's, it is presumed that a 15-lipoxygenase, most likely ALOX15 in humans, contributes to this metabolism. These products, termed n-3 Resolven D's (RvDn-3's), are: * RvD1n-3, RvD2n-3, and RvD3n-3; each of these products possesses potent anti-inflammatory activity (see ).


Linoleic acid

Human 15-LOX-1 prefers linoleic acid over arachidonic acid as its primary substrate, oxygenating it at carbon 13 to form 13(''S'')-hydroperoxy-9''Z'',11''E''-octadecenoic acid (13-HpODE or 13(''S'')-HpODE) which may then be reduce to the corresponding hydroxy derivative, 13(''S'')-HODE or 13-HODE (see
13-Hydroxyoctadecadienoic acid 13-Hydroxyoctadecadienoic acid (13-HODE) is the commonly used term for 13(''S'')-hydroxy-9''Z'',11''E''-octadecadienoic acid (13(''S'')-HODE). The production of 13(''S'')-HODE is often accompanied by the production of its stereoisomer, 13(''R'') ...
). In addition to 13(''S'')-HpODE, non-human 15-LOX1 orthologs such as mouse 12/15-LOX and soybean 15-LOX metabolize linoleic acid to 9-hydroperoxy-10''E'', 12''Z''-octadecenoic acid (9-HpODE or 9(''S'')-HpODE), which is rapidly converted to 9(''S'')-HODE (9-HODE) (see
9-Hydroxyoctadecadienoic acid 9-Hydroxyoctadecadienoic acid (or 9-HODE) has been used in the literature to designate either or both of two stereoisomer metabolites of the essential fatty acid, linoleic acid: 9(''S'')-hydroxy-10(''E''),12(''Z'')-octadecadienoic acid (9(''S' ...
). 13(''S'')-HODE acts through
peroxisome proliferator-activated receptor In the field of molecular biology, the peroxisome proliferator–activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating gene expression. PPARs play essential roles in regulating cel ...
s and the
TRPV1 The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the ''TRPV1'' gene. It was the first isolated member of ...
and human GPR132 receptors to stimulate a variety of responses related to monocyte maturation, lipid metabolism, and neuron activation (see ); 9(''S'')-HODE is a marker for diseases involving
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
and may contribute to this disease as well as to pain perception and
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
(see of 9-HODEs). The two HODEs can be further metabolized to their
ketone In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...
s, 13-oxo-9''Z'',11''E''-octadecenoic acid and 9-oxo-10''E'', 12''Z''-octadecenoic acid; these ketones have been implicated as
biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
s for and possible contributors to the inflammatory component of atherosclerosis,
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
,
steatohepatitis Steatohepatitis is a type of fatty liver disease, characterized by inflammation of the liver with concurrent fat accumulation in liver. Mere deposition of fat in the liver is termed steatosis, and together these constitute fatty liver changes. ...
, and other pathological conditions.


Dihomo-γ-linolenic acid

Human neutrophils, presumably using their ALOX 15, metabolize dihomo-γ-linolenic acid (8''Z'',11''Z'',14''Z''-eicosatrienoic acid) to 15''S''-hydroperoxy-8''Z'',11''Z'',13''E''-eicosatrienoic acid and 15''S''-hydroxy-8''Z'',11''Z'',13''E''-eicosatrienoic acid (15''S''-HETrE). 15''S''-HETrE possesses anti-inflammatory activity.


Gene manipulation studies

Mice made deficient in their 12/15-lipoxygenase gene (Alox15) exhibit a prolonged inflammatory response along with various other aspects of a pathologically enhanced inflammatory response in experimental models of
cornea The cornea is the transparency (optics), transparent front part of the eyeball which covers the Iris (anatomy), iris, pupil, and Anterior chamber of eyeball, anterior chamber. Along with the anterior chamber and Lens (anatomy), lens, the cornea ...
injury, airway inflammation, and
peritonitis Peritonitis is inflammation of the localized or generalized peritoneum, the lining of the inner wall of the abdomen and covering of the abdominal organs. Symptoms may include severe pain, swelling of the abdomen, fever, or weight loss. One pa ...
. These mice also show an accelerated rate of progression of atherosclerosis whereas mice made to overexpress 12/15-lipoxygenase exhibit a delayed rate of atherosclerosis development. Alox15 overexpressing rabbits exhibited reduced tissue destruction and bone loss in a model of
periodontitis Periodontal disease, also known as gum disease, is a set of inflammatory conditions affecting the tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen and red and may bleed. It is considered the main c ...
. Finally, Control mice, but not 12/15-lipoxygense deficient mice responded to eicospentaenoic acid administration by decreasing the number of lesions in a model of
endometriosis Endometriosis is a disease in which Tissue (biology), tissue similar to the endometrium, the lining of the uterus, grows in other places in the body, outside the uterus. It occurs in women and a limited number of other female mammals. Endomet ...
. These studies indicate that the suppression of inflammation is a major function of 12/15-lipoxygenase and the
Specialized proresolving mediators Specialization or Specialized may refer to: Academia * Academic specialization, may be a course of study or major at an academic institution or may refer to the field in which a specialist practices * Specialty (medicine), a branch of medical ...
it produces in rodents; although rodent 12/15-lipoxygenase differs from human ALOX15 in the profile of the PUFA metabolites that it produces as well as various other parameters (e.g. tissue distribution), these genetic studies allow that human ALOX15 and the specialized proresolving mediators it produces may play a similar major anti-inflammatory function in humans.


Clinical significance


Inflammatory diseases

À huge and growing number of studies in animal models suggest that 15-LOX-1 and its lipoxin, resolvin, and protectin metabolites (see
Specialized proresolving mediators Specialization or Specialized may refer to: Academia * Academic specialization, may be a course of study or major at an academic institution or may refer to the field in which a specialist practices * Specialty (medicine), a branch of medical ...
) to inhibit, limit, and resolve diverse inflammatory diseases including
periodontitis Periodontal disease, also known as gum disease, is a set of inflammatory conditions affecting the tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen and red and may bleed. It is considered the main c ...
,
peritonitis Peritonitis is inflammation of the localized or generalized peritoneum, the lining of the inner wall of the abdomen and covering of the abdominal organs. Symptoms may include severe pain, swelling of the abdomen, fever, or weight loss. One pa ...
,
sepsis Sepsis is a potentially life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage of sepsis is followed by suppression of the immune system. Common signs and s ...
, and other pathogen-induced inflammatory responses; in
eczema Dermatitis is a term used for different types of skin inflammation, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened ...
,
arthritis Arthritis is a general medical term used to describe a disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, Joint effusion, swelling, and decreased range of motion of ...
,
asthma Asthma is a common 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 wh ...
,
cystic fibrosis Cystic fibrosis (CF) is a genetic disorder inherited in an autosomal recessive manner that impairs the normal clearance of Sputum, mucus from the lungs, which facilitates the colonization and infection of the lungs by bacteria, notably ''Staphy ...
,
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
, and
adipose Adipose tissue (also known as body fat or simply fat) is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, Blood vessel, vascular endothel ...
tissue inflammation; in the
insulin resistance Insulin resistance (IR) is a pathological response in which cells in insulin-sensitive tissues in the body fail to respond normally to the hormone insulin or downregulate insulin receptors in response to hyperinsulinemia. Insulin is a horm ...
that occurs in obesity that is associated with
diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
and the
metabolic syndrome Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Metabolic syndro ...
; and in
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
. While these studies have not yet been shown to translate to human diseases, first and second generation synthetic resolvins and lipoxins, which unlike their natural analogs, are relatively resistant to metabolic inactivation, have been made and tested as inflammation inhibitors in animal models. These synthetic analogs may prove to be clinically useful for treating the cited human inflammatory diseases. By metabolizing the ω-3 polyunsaturated fatty acids, eicosapentaenoic acid and docosahexaenoic acid, into 17-HpDHA, 17-HDHA, and the resolvins and protectins, 15-LOX-1's metabolic action is thought to be one mechanism by which dietary ω-3 polyunsaturated fatty acids, particularly
fish oil Fish oil is oil derived from the tissues of oily fish. Fish oils contain the omega−3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), precursors of certain eicosanoids that are known to reduce inflammation in the bod ...
, act to ameliorate inflammation, inflammation-related diseases, and certain cancers.


Asthma

15-LOX-1 and its 5-oxo-15-hydroxy-ETE and
eoxin Eoxins are proposed to be a family of proinflammatory eicosanoids (signaling compounds that regulate inflammatory and immune responses). They are produced by human eosinophils (a class of white blood cells), mast cells, the L1236 Reed–Sternberg ...
metabolites have been suggested as potential contributors to, and therefore targets for the future study and treatment of, human allergen-induced
asthma Asthma is a common 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 wh ...
, aspirin-induced asthma, and perhaps other allergic diseases.


Cancer

In colorectal, breast, and kidney cancers, 15-LOX-1 levels are low or absent compared to the cancers' normal tissue counterparts and/or these levels sharply decline as the cancers progress. These results, as well as a 15-LOX-1 transgene study on colon cancer in mice suggests but do not prove that 15-LOX-1 is a
tumor suppressor A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell (biology), cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results ...
. By metabolizing ω-3 polyunsaturated fatty acids, eicosapentaenoic acid and docosahexaenoic acid, into lipoxins and resolvins, 15-LOX-1 is thought to be one mechanism by which dietary ω-3 polyunsaturated fatty acids, particularly fish oil, may act to reduce the incidence and/or progression of certain cancers. Indeed, the ability of docosahexaenoic acid to inhibit the growth of cultured human prostate cancer cells is totally dependent upon the expression of 15-LOX-1 by these cells and appears due to this enzyme's production of docosahexaenoic acid metabolites such as 17(S)-HpETE, 17(S)-HETE, and/or and, possibly, an isomer of protectin DX (10S,17S-dihydroxy-4Z,7Z,11E,13Z,15E,19Z-docosahexaenoic acid) Kelavkar et.al have shown that aberrant overexpression of 15-LO-1 occurs in human PCa, particularly high-grade PCa, and in high-grade prostatic intraepithelial neoplasia (HGPIN), and that the murine orthologue is increased in SV40-based genetically engineered mouse (GEM) models of PCa, such as LADY and TRansgenic Adenocarcinoma of Mouse Prostate. Targeted overexpression of h15-LO-1 (a gene overexpressed in human PCa and HGPIN) to mouse prostate is sufficient to promote epithelial proliferation and mPIN development. These results support 15-LO-1 as having a role in prostate tumor initiation and as an early target for dietary or other prevention strategies. The FLiMP mouse model should also be useful in crosses with other GEM models to further define the combinations of molecular alterations necessary for PCa progression.


Notes


See also

*
15-Hydroxyicosatetraenoic acid 15-Hydroxyeicosatetraenoic acid (also termed 15-HETE, 15(''S'')-HETE, and 15''S''-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. Various cell types metabolize arachidonic acid to 15(''S'')-hydroperoxyeicosatetraenoic acid (15(''S'' ...
*
12-Hydroxyeicosatetraenoic acid 12-Hydroxyeicosatetraenoic acid (12-HETE) is a derivative of the 20 carbon polyunsaturated fatty acid, arachidonic acid, containing a hydroxyl residue at carbon 12 and a 5''Z'',''8Z'',10''E'',14''Z'' cis–trans configuration (Z=cis, E=trans) in ...


References

*


Further reading

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External links

* {{Portal bar, Biology, border=no EC 1.13.11