ALOX15 (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other

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 auto ...

s, a seminal

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 ...

in the metabolism of

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 ...

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 (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 ...

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 83 million base pairs (the building material of DNA) and represents between 2.5 and 3% of the total D ...

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

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 ...

and 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. ...

coding for a 75

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 ...

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. Fun ...

(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 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

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

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 (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...

s and

reticulocytes 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 developing into mat ...

, cells, bronchial airway epithelial cells, mammary epithelial cells, the Reed-Sternberg cells 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 patient's lymph nodes. The condition wa ...

cornea 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 power ...

l epithelial cells, 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 ...

; it is less strongly expressed in alveolar

macrophages 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 ce ...

, tissue

mast cells 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 ...

, tissue

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 ...

, circulating blood

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 ...

, vascular

endothelial cells 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 ...

, joint

Synovial membrane The synovial membrane (also known as the synovial stratum, synovium or stratum synoviale) is a specialized connective tissue that lines the inner surface of capsules of synovial joints and tendon sheath. It makes direct contact with the fibrous ...

cells,

seminal fluid Semen, also known as seminal fluid, is an organic bodily fluid created to contain spermatozoa. It is secreted by the gonads (sexual glands) and other sexual organs of male or hermaphroditic animals and can fertilize the female ovum. Semen 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 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 ...

s. They commonly catalyze the attachment of molecular oxygen as a

peroxy In chemistry, peroxides are a group of compounds with the structure , where R = any element. The group in a peroxide is called the peroxide group or peroxo group. The nomenclature is somewhat variable. The most common peroxide is hydrogen ...

residue to

polyunsaturated fatty acids 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) 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 bound between their ω-13 and ω-12 carbons, human ALOX15 forms ω-6 peroxy intermediates; in PUFAs that do have this third double bound, 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 ( ) (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 nomenclature. ...

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 Co ...

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 () 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 ...

intermediate that is attacked by a water molecule to form epoxy-hydrpoxy 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 COOH(CH2)7CH=CHCH2CH=CH(CH2)4CH3. Both alkene groups are cis-trans isomerism, ''cis''. It is a fatty acid sometimes denoted 18:2 (n-6) or 18:2 ''cis''-9,12. A linoleate is a salt (chem ...

alpha-linolenic acid ''alpha''-Linolenic acid (ALA), also known as α-Linolenic acid (from Greek ''alpha'' meaning "first" and ''linon'' meaning flax), is an ''n''−3, or omega-3, essential fatty acid. ALA is found in many seeds and oils, including flaxseed, waln ...

, 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 with a 20-c ...

, and

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 ...

when presented not only as free acids but also when incorporated as

esters In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides are ...

phospholipids 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 ...

glycerides Glycerides, more correctly 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 ...

, or Cholesteryl esters. 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

s between carbons 5-6, 8-9, 11-12, and 14-15; these double bonds are in the cis (see

Cis–trans isomerism ''Cis''–''trans'' isomerism, also known as geometric isomerism or configurational isomerism, is a term used in chemistry that concerns the spatial arrangement of atoms within molecules. The prefixes "''cis''" and "''trans''" are from Latin: " ...

or Z as opposed to the 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 h ...

enzymes to their corresponding hydroxy analogs, 15(''S'')-HETE (see 15-Hydroxyeicosatetraenoic acid) and 12(''S'')-HETE (see 12-Hydroxyeicosatetraenoic acid). 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 (BLT1 ...

, 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 tran ...

, and at high concentrations cause cells to generate toxic

reactive oxygen species In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen () p ...

; 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-Hydroxyicosatetraenoic acid#15(S)-HpETE and 15(S)-HETE). 15(''S'')-HpETE and 15(''S'')-HETE are esterified into membrane

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 Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

membrane phospholipids during the maturation of

red blood cell 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 (see

erythropoiesis Erythropoiesis (from Greek 'erythro' meaning "red" and 'poiesis' "to make") is the process which produces red blood cells (erythrocytes), which is the development from erythropoietic stem cell to mature red blood cell. It is stimulated by decrea ...

) 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 (LX)A4, LXB4, AT-LXA4, and AT-LXB4; these metabolites are members of the specialized proresolving mediator class of anti-inflammatory agents that contribute to the resolution of inflammatory responses and inflammation-based diseases in animal models and, potentially, humans (see

specialized proresolving 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). * Hepoxilin isomers (e.g. 1S-hydroxy-14S,15S-epoxy-5Z,8Z,12E-eicosatrienoic acid 4,15-HXA3and 13R-hydroxy-14S,15S-epoxy-5Z,8Z,11Z-eicosatrienoic acid 4,15-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 ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...

secretion (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 eicosanoid ...

s). * Eoxins (e.g. eoxin C4, 14,15-eoxin D4, and eoxin E4) which have pro-inflammatory actions and contribute to 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 ...

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 ...

attacks, and other

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 ...

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 lymphocytes, where multinucleated Reed–Sternberg cells (RS cells) are present in the patient's lymph nodes. The condition w ...

(see

Eoxins 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 c ...

). * 8(''S''),15(''S'')-dihydroxy-5''Z'',9''E'',ll''Z'',13''E''-eicosatetraenoic acid (8(''S''),15(''S'')-diHETE), an inhibitor of human platelet aggregation (see Dihydroxy-E,Z,E-PUFA). * 5(''S''),15(''S'')-dihydroxy-6''Z'',8''E'',ll''E'',13''Z''-eicosatetraenoic acid (5(''S''),15(''S'')-diHETE) and its 5-

ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...

analog, 5-oxo-15(''S'')-hydroxy-ETE. These are weak and potent, respectively, stimulators of human

neutrophil 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 ...

, 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 conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also inf ...

chemotaxis 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 ...

and thereby possible contributors to human allergic and non-allergic

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 ...

responses (see 5-Hydroxyicosatetraenoic acid#Inflammation and 5-Hydroxyicosatetraenoic acid#Allergy). * 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., angiogenesis ...

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 Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...

reactions (see 15-Hydroxyicosatetraenoic acid#15-oxo-ETE). 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 p ...

GPR31 G-protein coupled receptor 31 also known as 12-(S)-HETE receptor is a protein that in humans is encoded by the ''GPR31'' gene. The human gene is located on chromosome 6q27 and encodes a G-protein coupled receptor protein composed of 319 amino aci ...

and the

; 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 rece ...

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 prostanoid receptors and was the first eicosanoid rec ...

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 act ...

and

Prostaglandin H2 Prostaglandin H2 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 conversion from Arachidonic acid to P ...

(see 12-Hydroxyeicosatetraenoic acid#Receptor targets and mechanisms of action). 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 12-Hydroxyeicosatetraenoic acid#Activities and possible clinical significance). 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 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. The process is the opposite of vasoconstriction, ...

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 eicosanoid ...

. * 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 Leukotriene B4 (LTB4) is a leukotriene involved in inflammation. It is produced from leukocytes in respo ...

receptor,

(BLT2) but not its

Leukotriene B4 receptor The leukotriene B4 receptors (BLTRs) include the following two receptors: * Leukotriene B4 receptor 1 (BLTR1) * Leukotriene B4 receptor 2 (BLTR2) See also * Eicosanoid receptor * Leukotriene receptor The leukotriene (LT) receptors are G protein ...

1 (BLT1). This allows the possibility that 12-oxo-ETE contributes to the pro-inflammatory and other activities that BLT2 regulates (see 12-HETE#Inflammation and inflammatory diseases and

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 specialized proresolving mediators#DHA-derived Resolvins). One or both of these products may be further metabolized enzymatically to: * Resolvin Ds (RvDs), i.e. RvD-1, RvD2, RvD3, RvD4, RvD5, and RvD6 (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 t ...

and specialized proresolving mediators#DHA-derived Resolvins) and protectin Ds (PDs), i.e. PD1, PDX, 20-hydroxy-PD1, 17-epi-PD1, and 10-epi-PD1 (see neuroprotectin D1 and specialized proresolving mediators#DHA-derived protectins/neuroprotectins). These products are members of, and have a wide range of activities common to, the

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 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 ...

, 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 Specialized proresolving mediators#EPA-derived resolvins (i.e. RvE)).

n-3 Docosaexaenoic 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, see

clupanodonic acid Docosapentaenoic acid (DPA) designates any straight chain 22:5 fatty acid, that is a straight chain open chain type of polyunsaturated fatty acid (PUFA) which contains 22 carbons and 5 double bonds. DPA is primarily used to designate two isomers, ...

) 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 (RvD_n-3's), are: * RvD1_n-3, RvD2_n-3, and RvD3_n-3; each of these products possesses potent anti-inflammatory activity (see Specialized proresolving mediators#n-3 DPA-derived resolvins).

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''-octadecaenoic 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). 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''-octadecaenoic 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 the expression of genes. PPARs play essential roles in the regu ...

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 th ...

and human

GPR132 G protein coupled receptor 132, also termed G2A, is classified as a member of the proton sensing G protein coupled receptor (GPR) subfamily. Like other members of this subfamily, i.e. GPR4, GPR68 (OGR1), and GPR65 (TDAG8), G2A is a G protein c ...

receptors to stimulate a variety of responses related to monocyte maturation, lipid metabolism, and neuron activation (see 13-Hydroxyoctadecadienoic acid##Activities of 13-HODEs); 9(''S'')-HODE is a marker for diseases involving

and may contribute to this disease as well as to pain perception and

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 ...

(see 9-Hydroxyoctadecadienoic acid##Biological and clinical relevancy of 9-HODEs). The two HODEs can be further metabolized to their

ketones In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bon ...

, 13-oxo-9''Z'',11''E''-octadecaenoic acid and 9-oxo-10''E'', 12''Z''-octadecaenoic acid; these ketones have been implicated as

biomarkers 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, p ...

for and possible contributors to the inflammatory component of atherosclerosis,

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

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. T ...

, and other pathological conditions.

Dihomo-γ-linolenic acid

Human neutrophils, presumably using their ALOX 15, metabolize

Dihomo-γ-linolenic acid Dihomo-γ-linolenic acid (DGLA) is a 20-carbon ω−6 fatty acid. (also called, cis,cis,cis-8,11,14-Eicosatrienoic acid) In physiological literature, it is given the name 20:3 (ω−6). DGLA is a carboxylic acid with a 20-carbon chain and thre ...

(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

injury, airway inflammation, and

peritonitis Peritonitis is inflammation of the localized or generalized peritoneum, the lining of the inner wall of the abdomen and cover of the abdominal organs. Symptoms may include severe pain, swelling of the abdomen, fever, or weight loss. One part or ...

. 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 caus ...

. 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 of the female reproductive system in which cells similar to those in the endometrium, the layer of tissue that normally covers the inside of the uterus, grow outside the uterus. Most often this is on the ovaries, f ...

. These studies indicate that the suppression of inflammation is a major function of 12/15-lipoxygenase and the

Specialized proresolving 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 ...

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

) to inhibit, limit, and resolve diverse inflammatory diseases including

sepsis Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...

, and other pathogen-induced inflammatory responses; in

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 ...

arthritis Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...

cystic fibrosis Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. O ...

, and

adipose Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular ...

tissue inflammation; in the

insulin resistance Insulin resistance (IR) is a pathological condition in which cell (biology), cells fail to respond normally to the hormone insulin. Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood gluco ...

that occurs in obesity that is associated with

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

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 syndrome ...

; and in

. 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 body a ...

, act to ameliorate inflammation, inflammation-related diseases, and certain cancers.

Asthma

15-LOX-1 and its 5-oxo-15-hydroxy-ETE and eoxin metabolites have been suggested as potential contributors to, and therefore targets for the future study and treatment of, human allergen-induced

, 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. 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

References

External links

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

Nomenclature

Tissue distribution

Enzyme activities

Lipoxygenase activity

Lipohydroperoxidase activity

Leukotriene synthase activity

Substrates, substrate metabolites, and metabolite activities

Arachidonic acid

Docosahexaenoic acid

Eicosapentaenoic acid

n-3 Docosaexaenoic acid

Linoleic acid

Dihomo-γ-linolenic acid

Gene manipulation studies

Clinical significance

Inflammatory diseases

Asthma

Cancer

Notes

See also

References

Further reading

External links