5-Hydroxyeicosatetraenoic acid (5-HETE, 5(''S'')-HETE, or 5''S''-HETE) is an

eicosanoid Eicosanoids are lipid signaling, signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosa ...

, i.e. a metabolite of

arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega−6 fatty acid 20:4(ω−6), or 20:4(5,8,11,14). It is a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes. Together with omega−3 fatty acids an ...

. It is produced by diverse cell types in humans and other animal species. These cells may then metabolize the formed 5(''S'')-HETE to 5-oxo-eicosatetraenoic acid (5-oxo-ETE), 5(''S''),15(''S'')-dihydroxyeicosatetraenoic acid (5(''S''),15(''S'')-diHETE), or 5-oxo-15-hydroxyeicosatetraenoic acid (5-oxo-15(''S'')-HETE). 5(''S'')-HETE, 5-oxo-ETE, 5(''S''),15(''S'')-diHETE, and 5-oxo-15(''S'')-HETE, while differing in potencies, share a common mechanism for activating cells and a common set of activities. They are therefore a family of structurally related metabolites. Animal studies and a limited set of human studies suggest that this family of metabolites serve as

hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...

-like

autocrine Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with ...

and

paracrine signalling In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as para ...

agents that contribute to the up-regulation of acute inflammatory and

allergic 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 hay fever, food allergies, atopic dermatitis, alle ...

responses. In this capacity, these metabolites may be members of the

innate immune system The innate immune system or nonspecific immune system is one of the two main immunity strategies in vertebrates (the other being the adaptive immune system). The innate immune system is an alternate defense strategy and is the dominant immune s ...

. ''

In vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

'' studies suggest that 5(''S'')-HETE and/or other of its family members may also be active in promoting the growth of certain types of cancers, in simulating bone reabsorption, in signaling for the secretion of

aldosterone Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays ...

and

progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...

, in triggering

parturition Birth is the act or process of bearing or bringing forth offspring, also referred to in technical contexts as parturition. In mammals, the process is initiated by hormones which cause the muscular walls of the uterus to contract, expelling the f ...

, and in contributing to other responses in animals and humans. However, the roles of 5(''S'')-HETE family members in these responses as well as in inflammation and allergy are unproven and will require much further study. Among the 5(''S'')-HETE family members, 5(''S'')-HETE takes precedence over the other members of this family because it was the first to be discovered and has been studied far more thoroughly. However, 5-oxo-ETE is the most potent member of this family and therefore may be its critical member with respect to

physiology Physiology (; ) is the science, scientific study of function (biology), functions and mechanism (biology), mechanisms in a life, living system. As a branches of science, subdiscipline of biology, physiology focuses on how organisms, organ syst ...

and

pathology Pathology is the study of disease. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in the context of modern medical treatme ...

. 5-OxoETE has gained attention in recent studies.

Nomenclature

5-Hydroxyeicosatetraenoic acid is more properly termed 5(''S'')-hydroxyicosatetraenoic acid or 5(''S'')-HETE) to signify the (''S'')

configuration Configuration or configurations may refer to: Computing * Computer configuration or system configuration * Configuration file, a software file used to configure the initial settings for a computer program * Configurator, also known as choice board ...

of its 5- hydroxy residue as opposed to its 5(''R'')-hydroxyicosatetraenoic acid (i.e., 5(''R'')-HETE)

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 ...

. Since 5(''R'')-HETE was rarely considered in the early literature, 5(''S'')-HETE was frequently termed 5-HETE. This practice occasionally continues. 5(''S'')-HETE's

IUPAC The International Union of Pure and Applied Chemistry (IUPAC ) is an international federation of National Adhering Organizations working for the advancement of the chemical sciences, especially by developing nomenclature and terminology. It is ...

name, (5''S'',6''E'',8''Z'',11''Z'',14''Z'')-5-hydroxyicosa-6,8,11,14-tetraenoic acid, defines 5(''S'')-HETE's structure unambiguously by notating not only its ''S''-hydroxyl chirality but also the

cis–trans isomerism ''Cis''–''trans'' isomerism, also known as geometric isomerism, describes certain arrangements of atoms within molecules. The prefixes "''cis''" and "''trans''" are from Latin: "this side of" and "the other side of", respectively. In the cont ...

geometry for each of its 4

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; E signifies trans and Z signifies cis double bond geometry. The literature commonly uses an alternate but still unambiguous name for 5(''S'')-HETE viz., 5(''S'')-hydroxy-6''E'',8''Z'',11''Z'',14''Z''-eicosatetraenoic acid.

History of discovery

The Nobel laureate, Bengt I. Samuelsson, and colleagues first described 5(''S'')-HETE in 1976 as a metabolite of arachidonic acid made by rabbit

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. Biological activity was linked to it several years later when it was found to stimulate human neutrophil rises in cytosolic calcium,

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 increases in their cell surface adhesiveness as indicated by their aggregation to each other. Since a previously discovered arachidonic acid metabolite made by neutrophils,

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 ...

(LTB₄), also stimulates human neutrophil calcium rises, chemotaxis, and auto-aggregation and is structurally similar to 5(''S'')-HETE in being a 5(''S'')-hydroxy-eicosateraenoate, it was assumed that 5(''S'')-HETE stimulated cells through the same

cell surface receptor Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integra ...

s as those used by LTB₄ viz., the leukotriene B4 receptors. However, further studies in neutrophils indicated that 5(''S'')-HETE acts through a receptor distinct from that used by LTB₄ as well as various other neutrophil stimuli. This 5(''S'')-HETE receptor is termed the oxoeicosanoid receptor 1 (abbreviated as OXER1).

5(''S'')-HETE production

5(''S'')-HETE is a product of the cellular metabolism of the n-6

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 ...

, arachidonic acid (i.e. 5''Z'',8''Z'',11''Z'',14''Z''-eicosatetraenoic acid), by

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 ...

(also termed arachidonate-5-lipoxygenase, 5-lipoxygenase, 5-LO, and 5-LOX). ALOX5 metabolizes arachidonic acid to its

hydroperoxide Hydroperoxides or peroxols are Chemical compound, compounds of the form ROOH, where R stands for any group, typically Organic compound, organic, which contain the hydroperoxy functional group (). Hydroperoxide also refers to the hydroperoxide anio ...

derivative, arachidonic acid 5-hydroperoxide i.e. 5(''S'')-hydroperoxy-6''E'',8''Z'',11''Z'',14''Z''-eicosatetraenoic acid (5(''S'')-HpETE). 5(''S'')-HpETE may then be released and rapidly converted to 5(''S'')-HETE by ubiquitous cellular

peroxidase Peroxidases or peroxide reductases ( EC numberbr>1.11.1.x are a large group of enzymes which play a role in various biological processes. They are named after the fact that they commonly break up peroxides, and should not be confused with other ...

s: Alternatively, 5(''S'')-HpETE may be further metabolized to its

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 ...

, 5(6)-oxido-eicosatetraenoic acid viz.,

leukotriene A4 Leukotriene A4 (LTA4) is a leukotriene Leukotrienes are a family of eicosanoid inflammation, inflammatory mediators produced in leukocytes by the redox, oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid ...

(i.e. 5''S'',6''S''-epoxy-7''E'',9''E'',11''Z'',14''Z''-eicosatetraenoic acid or 5''S''-5,6-oxido-7''E'',9''E'',11''Z'',14''Z''-eicosatetraenoic acid). Leukotriene A4 may then be further metabolized either to

by leukotriene A4 hydrolase or to

leukotriene C4 Leukotriene C4 (LTC4) is a leukotriene. LTC4 has been extensively studied in the context of allergy and asthma. In cells of myeloid origin such as mast cells, its biosynthesis is orchestrated by translocation to the nuclear envelope along with co ...

by leukotriene C4 synthase. Finally, leukotriene C4 may be metabolized to

leukotriene D4 Leukotriene D4 (LTD4) is one of the leukotrienes. Its main function in the body is to induce the contraction of smooth muscle, resulting in bronchoconstriction and vasoconstriction. It also increases vascular permeability. LTD4 is released b ...

and then to

leukotriene E4 Leukotriene E4 (LTE4) is a cysteinyl leukotriene involved in inflammation. It is known to be produced by several types of white blood cells, including eosinophils, mast cells, tissue macrophages, and basophils, and recently was also found to b ...

. The relative amounts of these metabolites made by specific cells and tissues depends in large part on the relative content of the appropriate enzymes. The selective synthesis of 5(''S'')-HETE (i.e. synthesis of 5(''S'')-HETE without concurrent synthesis of 5(''R'')-HETE) by cells is dependent on, and generally proportionate to, the presence and levels of its forming enzyme, ALOX5. Human ALOX5 is highly expressed in cells that regulate

innate immunity The innate immune system or nonspecific immune system is one of the two main immunity strategies in vertebrates (the other being the adaptive immune system). The innate immune system is an alternate defense strategy and is the dominant immune s ...

responses, particularly those involved in

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'', '' ...

and

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 ...

. Examples of such cells include

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, B lymphocytes,

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 ...

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 ...

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 ...

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, and the monocyte-derived

foam cell Foam cells, also called lipid-laden macrophages, are a type of cell that contain cholesterol. These can form a plaque that can lead to atherosclerosis and trigger myocardial infarction and stroke. Foam cells are fat-laden cells with a M2 macro ...

s of

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 ...

tissues. ALOX5 is also expressed but usually at relatively low levels in many other cell types. The production of 5(''S'')-HETE by these cells typically serves a physiological function. However, ALOX5 can become overexpressed at high levels in certain types of human cancer cells such as those of the prostate, lung, colon, colorectal and pancreatic as a consequence of their

malignant transformation Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as ''malignant degeneration'' of a previously existing benign tumor. Causes There are ...

. In these cells, the ALOX5-dependent production of 5(''S'')-HETE appears to serve a pathological function viz., it promotes the growth and spread of the cancer cells. 5(''S'')-HETE may also be made in combination with 5(''R'')-HETE along with numerous other ''(S,R)''-hydroxy

s as a consequence of the non-enzymatic oxidation reactions. Formation of these products can occur in any tissue subjected to

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 ...

5(''S'')-HETE metabolism

In addition to its intrinsic activity, 5(''S'')-ETE can serve as an intermediate that is converted to other bioactive products. Most importantly, 5-Hydroxyeicosanoid dehydrogenase (i.e. 5-HEDH) converts the 5-hydroxy residue of 5(''S'')-HETE to a

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 ( ...

residue to form 5-oxo-eicosatetraenoic acid (i.e. 5-oxo-6''E'',8''Z'',11''Z'',14''Z''-eicosatetraenoate, abbreviated as 5-oxo-ETE). 5-HEDH is a reversibly acting NADP⁺/

NADPH Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require N ...

-dependent enzyme that catalyzes to following reaction: 5-HEDH acts bi-directionally: it preferentially oxygenates 5(''S'')-HETE to 5-oxo-ETE in the presence of excess NADH⁺ but preferentially reduces 5-oxo-ETE back to 5(''S'')-HETE in the presence of excess NADPH. Since cells typically maintain far higher levels of NADPH than NADP⁺, they usually make little or no 5-oxo-ETE. When undergoing

, however, cells contain higher levels of NADH⁺ than NADPH and make 5-oxo-ETE preferentially. Additionally, ''

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

'' studies indicate that cells can transfer their 5(''S'')-HETE to cells that contain high levels of 5-NEDH and NADP⁺ and therefore convert the transferred 5(''S'')-HETE to 5-oxo-ETE. It is suggested that 5-oxo-ETE forms preferentially ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

'' under conditions of

or conditions where

-rich cells can transfer their 5(''S'')-HETE to cells epithelial, endothelial, dendritic, and certain (e.g. prostate, breast, and lung) cancer cells which display little or no ALOX5 activity but have high levels of 5-NEDH and NADP⁺. Since 5-oxo-ETE is 30- to 100-fold more potent than 5(''S'')-HETE, 5-HEDH main function may be to increase the biological impact of 5-HETE production. Cells metabolize 5-(''S'')-HETE in other ways. They may use: *An

acyltransferase Acyltransferase is a type of transferase enzyme that acts upon acyl In chemistry, an acyl group is a moiety derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids. It contains a double-bonded oxygen ...

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 ...

ify 5(''S'')-HETE into their 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. This reaction may serve to storing 5(''S'')-HETE for its release during subsequent cell stimulation and/or alter the properties of cell membranes in functionally important ways. *A

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

, probably CYP4F3, to metabolize 5(''S'')-HETE to 5(''S''),20-dihydroxy-eicosatetraenoate (5,20-diHETE). Since 5,20-diHETE is ~50- to 100-fold weaker than 5(''S'')-HETE in stimulating cells, this metabolism is proposed to represent a pathway for 5(''S'')-HETE inactivation. *

ALOX15 ALOX15 (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically import ...

to metabolize 5(''S'')-HETE to 5(''S''),15(''S'')-dihydroxy-eicosatetraenoate (5,15-diHETE). 5,15-diHETE is ~3- to 10-fold weaker than 5(''S'')-HETE in stimulating cells. *12-Lipoxygenase (i.e.

ALOX12 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 ...

) to metabolize 5(''S'')-HETE to 5(''S''),12(''S'')-diHETE. The activity of this product has not yet been fully evaluated. * Cyclooxygenase-2 to metabolize 5(''S'')-HETE to 5(''S''),15(''R'')-diHETE and 5(''S''),11(''R'')-diHETE. The activity of these products have not yet been fully evaluated. *

Aspirin Aspirin () is the genericized trademark for acetylsalicylic acid (ASA), a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and inflammation, and as an antithrombotic. Specific inflammatory conditions that aspirin is ...

-treated cyclooxygenase-2 to metabolize 5(''S'')-HETE to 5(''S''),15(''R'')-diHETE. The activity of this product has not yet been fully evaluated. Alternate pathways that make some of the above products include the: a) metabolism of 5(''S'')-HpETE to 5-oxo-ETE by

(CYP) enzymes such as

CYP1A1 Cytochrome P450, family 1, subfamily A, polypeptide 1 is a protein that in humans is encoded by the ''CYP1A1'' gene. The protein is a member of the cytochrome P450 superfamily of enzymes. Function Metabolism of xenobiotics and drugs CYP1A1 is ...

CYP1A2 Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the ''CYP1A2'' gene. Function ...

, CYP1B1, and CYP2S1; b) conversion of 5-HETE to 5-oxo-ETE non-enzymatically by

heme Heme (American English), or haem (Commonwealth English, both pronounced /Help:IPA/English, hi:m/ ), is a ring-shaped iron-containing molecule that commonly serves as a Ligand (biochemistry), ligand of various proteins, more notably as a Prostheti ...

or other dehydrating agents; c) formation of 5-oxo-15(''S'')-hydroxy-ETE through 5-HEDH-based oxidation of 5(''S''),15(''S'')-dihydroxyicosatetraenoate; d) formation of 5(''S''),15(''R'')-dihydroxy-eicosatetraenoate by the attack of ALOX5 on

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'' ...

(15(''S'')-HETE); e) formation of 5-oxo-15(''S'')-hydroxy-eicosatetreaenoate (''5-oxo-15(''S'')-hydroxy-ETE'') by the arachidonate 15-lipoxygenase-1-based or arachidonate 15-lipoxygenase-2-based metabolism of 5-oxo-ETE; and f) conversion of 5(''S'')-HpETE and 5(''R'')-HpETE to 5-oxo-ETE by the action of a mouse

50-60

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 ...

cytosolic protein.

Mechanism of action

The OXER1 receptor

5(''S'')-HETE family members share a common receptor target for stimulating cells that differs from the receptors targeted by the other major products of ALOX5, i.e.,

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 ...

A4, and

B4. It and other members of the 5(''S'')-HETE family stimulate cells primarily by binding and thereby activating a dedicated

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 ...

, the oxoeicosanoid receptor 1 (i.e. OXER1, also termed the OXE, OXE-R, hGPCR48, HGPCR48, or R527 receptor). OXER1 couples to the

G protein G proteins, also known as guanine nucleotide-binding proteins, are a Protein family, family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell (biology), ...

complex composed of the

Gi alpha subunit Gi protein alpha subunit is a family of heterotrimeric G protein alpha subunits. This family is also commonly called the Gi/o (Gi /Go ) family or Gi/o/z/t family to include closely related family members. G alpha subunits may be referre ...

(Gαi) and

G beta-gamma complex The G beta-gamma complex (Gβγ) is a tightly bound dimeric protein complex, composed of one Gβ and one Gγ subunit, and is a component of heterotrimeric G proteins. Heterotrimeric G proteins, also called guanine nucleotide-binding proteins, co ...

(Gβγ); when bound to a 5-(''S'')-HETE family member, OXER1 triggers this G protein complex to dissociate into its Gαi and Gβγ components with Gβγ appearing to be the component responsible for activating the signal pathways which lead to cellular functional responses. The cell-activation pathways stimulated by OXER1 include those mobilizing calcium ions and activating MAPK/ERK,

p38 mitogen-activated protein kinases p38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases (MAPKs) that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell diffe ...

, cytosolic

phospholipase A2 The enzyme phospholipase A2 (EC 3.1.1.4, PLA2, systematic name phosphatidylcholine 2-acylhydrolase) catalyses the cleavage of fatty acids in position 2 of phospholipids, hydrolyzing the bond between the second fatty acid "tail" and the glycero ...

PI3K Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...

/ Akt, and

protein kinase C In cell biology, protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...

beta and epsilon. The relative potencies of 5-oxo-ETE, 5-oxo-15(''S'')-HETE, 5(''S'')-HETE, 5(''S''),15(''S'')-diHETE, 5-oxo-20-hydroxy-ETE, 5(''S''),20-diHETE, and 5,15-dioxo-ETE in binding to, activating, and thereby stimulating cell responses through the OXER1 receptor are ~100, 30, 5–10, 1–3, 1–3, 1, and <1, respectively.

Other receptors

Progress in proving the role of the 5-HETE family of agonists and their OXER1 receptor in human physiology and disease has been made difficult because mice, rats, and the other rodents so far tested lack OXER1. Rodents are the most common ''

'' models for investigating these issues. OXER1 is expressed in non-human primates, a wide range of other mammals, and various fish species and a model of allergic airways disease in cats, which express OXER1 and make 5-oxo-ETE, has recently been developed for such studies. In any event, cultured mouse MA-10

Leydig cell Leydig cells, also known as interstitial cells of the testes and interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle and produce testosterone in the presence of luteinizing hormone (LH). They are polyhedral ...

s, while responding to 5-oxo-ETE, lack OXER1. It is suggested that this cell's, as well as mouse and other rodent, responses to 5-oxo-ETE are mediated by a receptor closely related to OXER11 viz., the mouse niacin receptor 1, Niacr1. Niacr1, an

ortholog 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 speci ...

of OXER1, is a G protein-coupled receptor for

niacin Nicotinic acid, or niacin, is an organic compound and a vitamer of vitamin B3, an essential human nutrient. It is produced by plants and animals from the amino acid tryptophan. Nicotinic acid is also a prescription medication. Amounts f ...

, and responds to 5-oxo-ETE. It has also been suggested that one or more of the mouse hydroxycarboxylic acid (HCA) family of the G protein-coupled receptors, HCA1 ( GPR81), HCA2 ( GPR109A), and HCA3 ( GPR109B), which are G protein-coupled receptors for fatty acids may be responsible for rodent responses to 5-oxo-ETE. It is possible that human cellular responses to 5-oxo-ETE and perhaps its analogs may involve, at least in isolated instances, one or more of these receptors.

PPARγ

5-Oxo-15(''S'')-hydroxy-ETE and to a lesser extent 5-oxo-ETE but not 5(''S'')-HETE also bind to and activate

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 ...

(PPARγ). Activation of OXER1 receptor and PPARγ by the oxo analogs can have opposing effects on cells. For example, 5-oxo-ETE-bound OXER1 stimulates while 5-oxo-ETE-bound PPARγ inhibits the proliferation of various types of human cancer cell lines.

Other mechanisms

5(''S'')-HETE acylated into the

phosphatidylethanolamine Phosphatidylethanolamine (PE) is a class of phospholipids found in biological membranes. They are synthesized by the addition of cytidine diphosphate-ethanolamine to diglycerides, releasing cytidine monophosphate. S-Adenosyl methionine, ''S''-Ade ...

s fraction of human neutrophil membranes is associated with the inhibition of these cells from forming

neutrophil extracellular traps Neutrophil extracellular traps (NETs) are networks of extracellular fibers, primarily composed of DNA from neutrophils, which bind pathogens. Neutrophils are the immune system's first line of defense against infection and have conventionally bee ...

, i.e. extracellular DNA scaffolds which contain neutrophil-derived antimicrobial proteins that circulate in blood and have the ability to trap bacteria. It seems unlikely that this inhibition reflects involvement of OXER1. 5-Oxo-ETE relaxes pre-contracted human bronchi by a mechanism that does not appear to involve OXER1 but is otherwise undefined.

Clinical significance

Inflammation

5(''S'')-HETE and other family members were first detected as products of arachidonic acid made by stimulated human polymorphonuclear neutrophils ( PMN), a leukocyte blood cell type involved in host immune defense against infection but also implicated in aberrant pro-inflammatory immune responses such as arthritis; soon thereafter they found to be active also in stimulating these cells to migrate (i.e. chemotaxis), degranulate (i.e. release the anti-bacterial and tissue-injuring contents of their granules), produce bacteriocidal and tissue-injuring

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 ...

, and mount other pro-defensive as well as pro-inflammatory responses of the

. For example, the gram-negative bacterium, '' Salmonella tryphimurium'', and the outer surface of gram-negative bacteria

lipopolysaccharide Lipopolysaccharide (LPS), now more commonly known as endotoxin, is a collective term for components of the outermost membrane of the cell envelope of gram-negative bacteria, such as '' E. coli'' and ''Salmonella'' with a common structural archit ...

, promote the production of 5(''S'')-HETE and 5-oxo-ETE by human neutrophils. The family members stimulate another blood cell of the

system, the human

, acting synergistically with the pro-inflammatory CC chemokines, monocyte chemotactic protein-1 and monocyte chemotactic protein-3, to stimulate monocyte function. 5-Oxo-ETE also stimulates two other cell types that share responsibility with the PMN for regulating inflammation, the human

lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), an ...

and

. And, ''in vivo'' studies, the injection of 5-oxo-ETE into the skin of human volunteers causes the local accumulation of PMN and monocyte-derived

s. Furthermore, the production of one or more 5(''S'')-HETE family members as well as the expression of orthologs of the human OXER1 receptor occur in various mammalian species including dogs, cats, cows, sheep, elephants, pandas, opossums, and ferrets and in several species of fish; for example, cats undergoing experimentally induced asthma accumulate 5-oxo-ETE in their lung lavage fluid, feline leucocytes make as well as respond to 5-oxo-ETE by an oxer1-dependent mechanism; and an OXER1 ortholog and, apparently, 5-oxo-ETE are necessary for the inflammatory response to tissue damage caused by osmolarity insult in

zebrafish The zebrafish (''Danio rerio'') is a species of freshwater ray-finned fish belonging to the family Danionidae of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (an ...

. These results given above suggest that members of the 5-oxo-ETE family and the OXER1 receptor or its orthologs may contribute to protection against microbes, the repair of damaged tissues, and pathological inflammatory responses in humans and other animal species. However, an OXER1 ortholog is absent in mice and other rodents; while rodent tissues do exhibit responsiveness to 5-oxo-ETE, the lack of an oxer1 or other clear 5-oxoETE receptor in such valued animal models of diseases as rodents has impeded progress in our understanding of the physiological and pathological roles of 5-oxo-ETE.

Allergy

The following human cell types or tissues that are implicated in allergic reactivity produce 5-HETE (stereoisomer typically not defined): alveolar macrophages isolated from asthmatic and non-asthmatic patients,

basophil Basophils are a type of white blood cell White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and f ...

s isolated from blood and challenged with anti-IgE antibody,

s isolated from lung, cultured pulmonary artery endothelial cells, isolated human pulmonary vasculature, and allergen-sensitized human lung specimens challenged with specific allergen. Additionally, cultured human airway epithelial cell lines, normal bronchial epithelium, and bronchial smooth muscle cells convert 5(''S'')-HETE to 5-oxo-ETE in a reaction that is greatly increase by oxidative stress, which is a common component in allergic inflammatory reactions. Finally, 5-HETE is found in the

bronchoalveolar lavage fluid Bronchoalveolar lavage (BAL), also known as bronchoalveolar washing, is a diagnostic method of the lower respiratory system in which a bronchoscope is passed through the mouth or nose into an appropriate airway in the lungs, with a measured amou ...

of asthmatic humans and 5-oxo-ETE is found in the bronchoalveolar lavage fluid of cats undergoing allergen-induced bronchospasm. Among the 5-HETE family of metabolites, 5-oxo-ETE is implicated as the most likely member to contribute to allergic reactions. It has exceptionally high potency in stimulating the

, release of granule-bound tissue-injuring enzymes, and production of tissue-injuring reactive oxygen species of a cell type involved in allergic reactions, the human

eosinophil granulocyte 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 ...

. It is also exceptionally potent in stimulating eosinophils to activate cytosolic phospholipase A2 ( PLA2G4A) and possibly thereby to form

platelet-activating factor Platelet-activating factor, also known as PAF, PAF-acether or AGEPC (acetyl-glyceryl-ether-phosphorylcholine), is a potent phospholipid activator and mediator of many leukocyte functions, platelet aggregation and degranulation, inflammation, and an ...

(PAF) as well as metabolites of the 5-HETE family. PAF is itself a proposed mediator of human allergic reactions which commonly forms concurrently with 5-HETE family metabolites in human leukocytes and acts synergistically with these metabolites, particularly 5-oxo-ETE, to stimulate eosinophils. 5-Oxo-ETE also cooperates positively with at least four other potential contributors to allergic reactions,

RANTES Chemokine (C-C motif) ligand 5 (also CCL5) is a protein which in humans is encoded by the ''CCL5'' gene. The gene has been discovered in 1990 by ''in situ'' hybridisation and it is localised on 17q11.2-q12 chromosome. It is also known as RANTES ...

, eotaxin,

granulocyte macrophage colony-stimulating factor Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear, that is ...

, and

granulocyte colony-stimulating factor Granulocyte colony-stimulating factor (G-CSF or GCSF), also known as colony-stimulating factor 3 (CSF 3), is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream. Function ...

in stimulating human eosinophils and is a powerful stimulator of chemotaxis in another cell type contributing to allergic reactions, the human

basophil granulocyte Basophils are a type of white blood cell. Basophils are the least common type of granulocyte, representing about 0.5% to 1% of circulating white blood cells. They are the largest type of granulocyte. They are responsible for inflammatory reactio ...

. Finally, 5-oxo-ETE stimulates the infiltration of eosinophils into the skin of humans following its intradermal injection (its actions are more pronounced in asthmatic compared to healthy subjects) and when instilled into the trachea of Brown Norway rats causes eosinophils to infiltrate lung. These results suggest that the 5-oxo-ETE made at the initial tissue site of allergen insult acting through the OXER1 on target cells attracts circulating eosinophils and basophils to lung, nasal passages, skin, and possibly other sites of allergen deposition to contribute to asthma, rhinitis, and dermatitis, and other sites of allergic reactivity. The role of 5-HETE family agonists in the

bronchoconstriction Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath. Causes The condition has a number of causes, the most common bei ...

of airways (a hallmark of allergen-induced asthma) in humans is currently unclear. 5-HETE stimulates the contraction of isolated human bronchial muscle, enhances the ability of histamine to contract this muscle, and contracts guinea pig lung strips. 5-Oxo-ETE also stimulates contractile responses in fresh bronchi, cultured bronchi, and cultured lung smooth muscle taken from guinea pigs but in direct contrast to these studies is reported to relax bronchi isolated from humans. The latter bronchi contractile responses were blocked by cyclooxygenase-2 inhibition or a thromboxane A2 receptor antagonist and therefore appear mediated by 5-oxo-ETE-induced production of this thromboxane. In all events, the relaxing action of 5-oxo-ETE on human bronchi does not appear to involve OXER1.

Cancer

The 5-oxo-ETE family of agonists have also been proposed to contribute to the growth of several types of human cancers. This is based on their ability to stimulate certain cultured human cancer cell lines to proliferate, the presence of OXER1 mRNA and/or protein in these cell lines, the production of 5-oxo-ETE family members by these cell lines, the induction of cell death (i.e. apoptosis) by inhibiting 5-lipoxygenase in these cells, and/or the overexpression of 5-lipoxygenase in tissue taken from the human tumors. Human cancers whose growth has been implicated by these studies as being mediated at least in part by a member(s) of the 5-oxo-ETE family include those of the prostate, breast, lung, ovary, and pancreas.

Steroid production

5(''S'')-HETE and 5(''S'')-HpETE stimulate the production of

by cultured rat ovarian glomerulosa cells and enhance the secretion of progesterone and

testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...

by cultured rat testicular

s. Both metabolites are made by

cyclic adenosine monophosphate Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger, or cellular signal occurring within cells, that is important in many biological processes. cAMP is a derivative of adenosine tri ...

-stimulated MA-10 mouse Leydig cells; stimulate these cells to transcribe

steroidogenic acute regulatory protein The steroidogenic acute regulatory protein, commonly referred to as StAR (STARD1), is a transport protein that regulates cholesterol transfer within the mitochondria, which is the rate-limiting step in the production of steroid hormones. It is ...

, and in consequence produce the

steroid A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes t ...

s. The results suggest that trophic hormones (e.g., leutenizing hormone,

adrenocorticotropic hormone Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important ...

) stimulate these steroid producing cells to make 5(''S'')-HETE and 5(''S'')-HpEPE which in turn increase the synthesis of steroidogenic acute regulatory protein; the latter protein promotes the rate-limiting step in steroidogenesis, transfer of cholesterol from the outer to the inner membrane of mitochondria and thereby acts in conjunction with trophic hormone-induce activation of protein kinase A to make progesterone and testosterone. This pathway may also operate in humans: Human H295R adrenocortical cells do express OXER1 and respond to 5-oxo-ETE by an increasing the transcription of steroidogenic acute regulatory protein messenger RNA as well as the production of aldosterone and progesterone by an apparent OXER1-dependent pathway. Rat and mouse cells lack OXER1. It has been suggested that the cited mouse MA-10 cell responses to 5-oxo-ETE are mediated by an ortholog to OXER1, mouse niacin receptor 1, Niacr1, which is a G protein-coupled receptor mediating the activity of

, or by one or more of the mouse hydroxycarboxylic acid (HCA) family of the G protein-coupled receptors, HCA1 ( GPR81), HCA2 ( GPR109A), and HCA3 ( GPR109B), which are G protein-coupled receptors for fatty acids. In any event, Human H295R adrenocortical cells do express OXER1 and respond to 5-oxo-ETE by an increasing the transcription of steroidogenic acute regulatory protein messenger RNA as well as the production of aldosterone and progesterone by an apparent OXER1-dependent pathway.

Bone remodeling

In an ''in vitro'' mixed culture system, 5(''S'')-HETE is released by monocytes to stimulate, at sub-nanomolar concentrations, osteoclast-dependent bone reabsorption. It also inhibits morphogenetic protein-2 (BMP-2)-induced bone-like nodule formation in mouse calvarial organ cultures. These results allow that 5(''S'')-HETE and perhaps more potently, 5-oxo-ETE contribute to the regulation of

bone remodeling 300 px, Bone tissue is removed by osteoclasts, and then new bone tissue is formed by osteoblasts. Both processes utilize cytokine ( Insulin-like_growth_factor.html" ;"title="TGF-β, Insulin-like growth factor">IGF) signalling. In osteology, bone ...

Parturition

5(''S'')-HETE is: elevated in the human uterus during

labor Labour or labor may refer to: * Childbirth, the delivery of a baby * Labour (human activity), or work ** Manual labour, physical work ** Wage labour, a socioeconomic relationship between a worker and an employer ** Organized labour and the labour ...

; at 3–150 nM, increases both the rates of spontaneous contractions and overall contractility of myometrial strips obtained at term but prior to labor from human lower uterine segments; and in an ''in vitro'' system crosses either

amnion The amnion (: amnions or amnia) is a membrane that closely covers human and various other embryos when they first form. It fills with amniotic fluid, which causes the amnion to expand and become the amniotic sac that provides a protective envir ...

or intact amnion-chorion-decidua and thereby may along with

prostaglandin E2 Prostaglandin E2 (PGE2), also known as dinoprostone, is a naturally occurring prostaglandin with oxytocic properties that is used as a medication. Dinoprostone is used in labor induction, bleeding after delivery, termination of pregnanc ...

move from the amnion to uterus during labor in humans. These studies allow that 5(''S'')-HETE, perhaps in cooperation with established role of prostaglandin E2, may play a role in the onset of human labor.

Other actions

5(''S'')-HETE is reported to modulate

tubuloglomerular feedback In the renal physiology, physiology of the kidney, tubuloglomerular feedback (TGF) is a feedback system inside the kidneys. Within each nephron, information from the nephron#Renal tubule, renal tubules (a downstream area of the tubular fluid) is si ...

. 5(''S'')-HpETE is also reported to inhibit the -ATPase activity of synaptosome membrane preparations prepared from rat

cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...

and may thereby inhibit synapse-dependent communications between neurons. 5(''S'')-HETE acylated into phosphatidylethanolamine is reported to increase the stimulated production of

superoxide anion In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of th ...

and interleukin-8 release by isolated human neutrophils and to inhibit the formation of

(i.e. NETS); NETS trap blood-circulating bacteria to assist in their neutralization. 5(''S'')-HETE esterified to phosphatidylcholine and glycerol esters by human endothelial cells is reported to be associated with the inhibition of

prostaglandin Prostaglandins (PG) are a group of physiology, physiologically active lipid compounds called eicosanoids that have diverse hormone-like effects in animals. Prostaglandins have been found in almost every Tissue (biology), tissue in humans and ot ...

production.

References

External links

5-LOX Gene Atlas entry
{{DEFAULTSORT:Hydroxyeicosatetraenoic acid, 5-HETE Human physiology Animal physiology Fatty acids Eicosanoids Immunology Inflammations Cell signaling