15-Hydroxyeicosatetraenoic acid (also termed 15-HETE, 15(''S'')-HETE, and 15''S''-HETE) is an

eicosanoid Eicosanoids are 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. Eicosanoids are a s ...

, i.e. a metabolite of arachidonic acid. Various cell types metabolize arachidonic acid to 15(''S'')-hydroperoxyeicosatetraenoic acid (15(''S'')-HpETE). This initial

hydroperoxide Hydroperoxides or peroxols are compounds containing the hydroperoxide functional group (ROOH). If the R is organic, the compounds are called organic hydroperoxides. Such compounds are a subset of organic peroxides, which have the formula ROOR. ...

product is extremely short-lived in cells: if not otherwise metabolized, it is rapidly reduced to 15''(S)''-HETE. Both of these metabolites, depending on the cell type which forms them, can be further metabolized to 15-oxo-eicosatetraenoic acid (15-oxo-ETE), 5''S'',15''S''-dihydroxy-eicosatetraenoic acid (5(''S''),15(''S'')-diHETE), 5-oxo-15(''S'')-hydroxyeicosatetraenoic acid (5-oxo-15(''S'')-HETE, a subset of

specialized pro-resolving mediators Specialized pro-resolving mediators (SPM, also termed specialized proresolving mediators) are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of ...

viz., the

lipoxins 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-resolv ...

, a class of pro-inflammatory mediators, the

eoxin Eoxins are proposed to be a family of proinflammatory eicosanoids (signaling compounds that regulate inflammatory and immune responses). They are produced by human eosinophils (a class of white blood cells), mast cells, the L1236 Reed–Sternberg ...

s, and other products that have less well-defined activities and functions. Thus, 15(''S'')-HETE and 15(''S'')-HpETE, in addition to having intrinsic biological activities, are key precursors to numerous biologically active derivatives. Some cell types (e.g. platelets) metabolize arachidonic acid to the

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 ...

of 15(''S'')-HpETE, 15(''R'')-HpETE. Both stereoisomers may also be formed as result of the metabolism of arachidonic acid by cellular microsomes or as a result of arachidonic acid

auto-oxidation Autoxidation (sometimes auto-oxidation) refers to oxidations brought about by reactions with oxygen at normal temperatures, without the intervention of flame or electric spark. The term is usually used to describe the gradual degradation of organi ...

. Similar to 15(''S"'')-HpETEs, 15(''R'')-HpETE may be rapidly reduced to 15(''R'')-HETE. These ''R,S'' stereoisomers differ only in having their hydroxy residue in opposite orientations. While the two ''R'' stereoisomers are sometimes referred to as 15-HpETE and 15-HETE, proper usage should identify them as ''R'' stereoisomers. 15(''R'')-HpETE and 15(''R'')-HETE lack some of the activity attributed to their ''S'' stereoisomers but can be further to metabolized to bioactive products viz., the 15(''R'') class of

(also termed

epi-lipoxin Epi-lipoxins are trihydroxy (i.e. containing 3 hydroxyl residues) metabolites of arachidonic acid. They are 15''R''-epimers of their lipoxin counterparts; that is, the epi-lipoxins, 15-epi-lipoxin A4 (15-epi-LxA4) and 15-epi-lipoxin B4 (15-epi-L ...

s). 15(''S'')-HETE, 15(''S'')-HpETE, and many of their derivative metabolites are thought to have physiologically important functions. They appear to act as

hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are require ...

-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 p ...

and

paracrine signalling 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 paracrine factors diffuse over ...

agents that are involved in regulating inflammatory and perhaps other responses. Clinically, drugs that are stable analogs, and therefore mimic the anti-inflammatory actions of the lipoxins and drugs that block the production or actions of the pro-inflammatory eoxins may prove useful for treating acute and chronic

inflammatory disorders Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...

Nomenclature and stereoisomers

15(''S'')-HETE is unambiguously designated by a shortened version of its

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 viz., 15(''S'')-hydroxy-5''Z'',8''Z'',11''Z'',13''E''-eicosatetraenoic acid. In this terminology ''S'' refers to the

absolute configuration Absolute configuration refers to the spatial arrangement of atoms within a chiral molecular entity (or group) and its resultant stereochemical description. Absolute configuration is typically relevant in organic molecules, where carbon is bonde ...

of the chirality of the hydroxy

functional group In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the re ...

at carbon position 15. Its 15(''R'') enantiomer is designated 15(''R'')-hydroxy-5''Z'',8''Z'',11''Z'',13''E''-eicosatetraenoic acid. ''Z'' and ''E'' give the cis–trans isomerism about each

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 betwee ...

moiety Moiety may refer to: Chemistry * Moiety (chemistry), a part or functional group of a molecule ** Moiety conservation, conservation of a subgroup in a chemical species Anthropology * Moiety (kinship), either of two groups into which a society is ...

at carbon positions 5, 8, 11, and 13 with Z indicating cis and E indicating trans isomerism. Both stereoisomers are produced from their corresponding ''S'' and ''R'' 15-HpETE stereoisomers, i.e. 15(''S'')-hydroperoxy-5''Z'',8''Z'',11''Z'',13''E''-eicosatetraenoic acid (15(S)-HpETE) and (15''R'')-hydroperoxy-5''Z'',8''Z'',11''Z'',13''E''-eicosatetraenoic acid (15(R)-HpETE).

Production

Human cells release arachidonic acid (i.e. 5''Z'',8''Z'',11''Z'',14''Z''-eicosatetraenoic acid) from its storage site in

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 t ...

by reactions that involve phospholipase C and/or lipase enzymes. This release is stimulated or enhanced by cell stimulation. The freed arachidonic acid is then converted to 15-hydroperoxy/hydroxy products by one or more of the following five pathways. 15-Lipoxygenase-1: Cells metabolize arachidonic acid with 15-lipoxygenase-1 (i.e., 15-LO-1,

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

) to form 15(''S'')-HpETE as a major product and 12(''S'')-hydroperoxy-5''Z'',8''Z'',10''E'',15''Z''-eicosatetraenoic acid (12(''S'')-HpETE) and 14(''S''),15(''S'')-''trans''-oxido-5''Z'',8''Z'',11''Z''-14,15-leukotriene A4 as minor products; 15(''S'')-HpETE and 12(''S'')-HpETE are rapidly converted to 15(''S'')-HETE and 12(''S'')-hydroxy-5''Z'',8''Z'',10''E'',15''Z''-eicosatetraenoic acid ( 12(''S'')-hydroxyeicosatetraenoic acid), (i.e. 12(''S'')-HETE), respectively, or further metabolized through other enzyme pathways; 14(''S''),15(''S'')-''trans''-oxido-5''Z'',8''Z'',11''Z''-14,15-leukotriene A₄ is metabolized by 15-LO-1 to various isomers of 8,15(''S'')-dihydroxy-5''S'',8''S'',''11Z'',13''S''-eicosatetraenoic acids, e.g. 8,15(S)-LTB₄'s. 15-Lipoxygenase-2: Cells also used 15-lipoxygenase 2 (i.e. 15-LOX-2 or

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 ...

) to make 15(''S'')-HpETE and 15(''S'')-HETE. However this enzyme has a preference for metabolizing

linoleic acid Linoleic acid (LA) is an organic compound with the formula COOH(CH2)7CH=CHCH2CH=CH(CH2)4CH3. Both alkene groups are ''cis''. It is a fatty acid sometimes denoted 18:2 (n-6) or 18:2 ''cis''-9,12. A linoleate is a salt or ester of this acid. ...

rather than arachidonic acid. It therefore forms linoleic acid metabolites (e.g. 13-hydoxyperoxy/hydroxy-octadecadienoic and 9-hydroperoxy/hydroxyl-octadecadienoic acids) in greater amounts than 15(''S'')-HpETE and 15(''S'')-HETE. 15-LOX-2 also differs from 15-LOX-1 in that it does not make 12(''S'')-HpETE or the leukotriene A₄ isomer cited above. Cycloxygenase: Cells can use

prostaglandin-endoperoxide synthase 1 Cyclooxygenase 1 (COX-1), also known as prostaglandin G/H synthase 1, prostaglandin-endoperoxide synthase 1 or prostaglandin H2 synthase 1, is an enzyme that in humans is encoded by the ''PTGS1'' gene. In humans it is one of two cyclooxygenases. ...

(i.e. cyclooxygenenase-1 or COX-1) and

Prostaglandin-endoperoxide synthase 2 Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) (The HUGO official symbol is PTGS2; HGNC ID, HGNC:9605), also known as cyclooxygenase-2 or COX-2, is an enzyme that in humans is encoded by the ''PTGS2'' gene ...

(COX-2) to metabolize arachidonic acid primarily to

prostaglandins The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are deriv ...

but also to small amounts of 11(''R'')-HETE and a racemic mixture of 15-HETEs composed of ~22% 15(''R'')-HETE and ~78% 15(''S'')-HETE. When pretreated with

aspirin Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...

, however, COX-1 is inactive while COX-2 attacks arachidonic acid to produce almost exclusively 15(''R'')-HETE along with its presumed precursor 15(''R'')-HpETE. Microsome metabolism: Human and rat microsomal

cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

s, e.g. CYP2C19, metabolize arachidonic acid to a racemic mixture of 15-HETEs, i.e., 15(''R'',''S'')-HETEs, >90% of which is the 15(''R'') stereoisomer. Autoxidation: The spontaneous and non-enzymatically-induced

autoxidation Autoxidation (sometimes auto-oxidation) refers to oxidations brought about by reactions with oxygen at normal temperatures, without the intervention of flame or electric spark. The term is usually used to describe the gradual degradation of organi ...

of arachidonic acid yields 15(''R'',''S'')-hydroperoxy-5''Z'',8''Z'',11''Z'',13''E''-eicosatetraenoic acids. This non-enzymatic reaction is promoted in cells undergoing

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 ...

. Cells forming this racemic mixture of 15-hydroperoxy products may convert then to 15(''R,S'')-HETEs and other products. However, the uncontrolled overproduction of the 15-hydroperoxy products may react with other elements to produce cell injury.

Further metabolism

The newly formed products formed by the pathways cited in the previous section are bioactive but may also flow into down-stream pathways to form other metabolites with a different sets of bioactivity. The initially formed 15(''S'')-HpETE may be further metabolized by its parent cell or pass it to nearby cell by a process termed transcellular metabolism. 15(''S'')-HpETE may be: *Rapidly reduced to 15(''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. Functionality Peroxidases typically ca ...

reactions including those possessed by prostaglandin-endoperoxide synthase-1 and -2,

prostacyclin synthase Prostaglandin-I synthase () also known as prostaglandin I2 (prostacyclin) synthase (PTGIS) or CYP8A1 is an enzyme involved in prostanoid biosynthesis that in humans is encoded by the ''PTGIS'' gene. This enzyme belongs to the family of cytochrome ...

thromboxane synthase Thromboxane A synthase 1 (, platelet, cytochrome P450, family 5, subfamily A), also known as TBXAS1, is a cytochrome P450 enzyme that, in humans, is encoded by the ''TBXAS1'' gene. Function This gene encodes a member of the cytochrome P450 supe ...

, and various

glutathione peroxidase Glutathione peroxidase (GPx) () is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage. The biochemical function of glutathione peroxidase is to reduce lipid h ...

s. * Acylated into membrane phospholipids, particularly

Phosphatidylinositol Phosphatidylinositol (or Inositol Phospholipid) consists of a family of lipids as illustrated on the right, where red is x, blue is y, and black is z, in the context of independent variation, a class of the phosphatidylglycerides. In such molecul ...

s and

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 can ...

. The 15(S)-HpETE is bound primarily at the ''sn''-2 position of these phospholipids (see

Phospholipase A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. Acids trigger the release of bound calcium from cellular stores and the consequent increase in free cytosolic Ca2+, an essential step in ...

) and may be reduced to 15(''S'')-HETE thereby forming their 15(''S'')-HETE-bound phospholipoid analogs. Phosphotidylinositol phospholipids with 15(''S'')-HETE in the ''sn''-2 position can be attacked by phospholipase C to form corresponding

diglyceride A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. DAGs can act as su ...

s with 15(''S'')-HETE at their''sn''-2 positions. *Metabolized by 15-LO-1 to its 14,15-''trans''-epoxide, 14,15-trans-epoxide oxido-5''Z'',8''Z'',10''E'',13''E''-eicosatetraenoic acid (i.e.,

Eoxin Eoxins are proposed to be a family of proinflammatory eicosanoids (signaling compounds that regulate inflammatory and immune responses). They are produced by human eosinophils (a class of white blood cells), mast cells, the L1236 Reed–Sternberg ...

A₄ or EXA₄), and thereafter to 14(R)-glutothionyl-15(S)hydroxy-5''Z'',8''Z'',10''E'',13''E''-eicosatetraenoic acid (i.e. Eoxin C₄ or EXC₄) by

leukotriene C4 synthase Leukotriene C4 synthase is an enzyme that in humans is encoded by the ''LTC4S'' gene. The protein encoded by this gene, LTC4S (or glutathione S-transferase II) is an enzyme that converts leukotriene A4 and glutathione to create leukotriene C4. T ...

. EXC₄ contains

glutathione Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pe ...

(i.e. γ-L-glutamyl-L-cysteinylglycine) bound in the ''R'' configuration to carbon 14. EXC₄ is further metabolized by removal of the γ-L-glutamyl residue to form EXD₄ which is in turn further metabolized by removal of the glycine residue to form EXE₄. These metabolic transformations are similar to those in the pathway that metabolizes arachidonic acid to LTA₄, LTC₄, LTD₄, and LTE₄ and presumed to be conducted by the same enzymes (Eoxins are also termed 14,15-leukotrienes or 14,15-LTs). *Metabolized alternatively by 15-LO-1 to various 8,15-diHETEs including the two 8(R) and 8(S)

Diastereomer In stereochemistry, diastereomers (sometimes called diastereoisomers) are a type of stereoisomer. Diastereomers are defined as non-mirror image, non-identical stereoisomers. Hence, they occur when two or more stereoisomers of a compound have di ...

s of 8,15(''S'')-dihydroxy-5,9,11,13-eicosatetraenoic acid (8,15-leukotrienes B4) and to two isomeric

erythro In stereochemistry, diastereomers (sometimes called diastereoisomers) are a type of stereoisomer. Diastereomers are defined as non-mirror image, non-identical stereoisomers. Hence, they occur when two or more stereoisomers of a compound have dif ...

-14,15-dihydroxy-5-cis-8,10,12-eicosatetraenoic acids (14,15-leukotrienes B4). *Metabolized by 15-LOX-2 to 11(''S'')-hydroxy-14(''S''),15(''S'')-epoxy-5(''Z''),8(''Z''),12(''E'')-eicosatrienoic acid and 13(''R'')-hydroxy-14(''S''),15(''S'')-epoxy-5(''Z''),8(''Z''),11(''Z'')-eicosatrienoic acid; these two products are novel

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 produced by ALOX15 rather than ALOX12, the enzyme responsible for making the various other hepoxilins in humans. The two novel hepoxilins are termed respectively ''14,15-HXA₃'' and ''14,15-HXB₃''. 14,15-HXA₃ can be further metabolized by glutathione transferases to 11(''S''),15(''S'')-dihydroxy-14(''R'')-glutathionyl--(5''Z''),8(''Z''),12(''E'')eicosatrienoic acid (''14,15-HXA₃C'') which is then further metabolized to 11(''S''),15(''S'')-dihydroxy-14(''R'')-cysteinyl-glycyl-(5''Z''),8(''Z''),12(''E'')eicosatrienoic acid (''14,15-HXA₃D''). *

Isomerized In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers. Is ...

to 15(''S'')-hydroxy-11,12-cis-epoxy-5''Z'',8''Z'',13''E''-eicosatrienoic acid (i.e., 15-H-11,12-EETA) by a hydroperoxide isomerase activity and then to 11,12,15-trihydroxy-5''Z'',8Z''12E''-eicosatrienoic acid (i.e. 11,12,15-THETA) and 11,14,15-trihydroxy-5''Z'',8''Z'',12''E''-eicosatrienoic acid (i.e., 11,14,15-THETA) by a soluble epoxide hydrolase activity or, by acid in a non-enzymatic reaction (the R, S configuration of the hydroxy residues in the latter two metabolites has not been defined). *Isomerized to ''threo'' and ''erythro'' diastereoisomers of 13-hydroxy-14,15-cis-epoxy-5''Z'',8''Z'',11''Z''-eicosatrienoic acid (i.e., 15-H-11,12-EETA) by a hydroperoxide isomerase activity, possibly a

Cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

, i.e. CYP2J2. *Metabolized 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 ...

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 Cytochrome P450 1B1 is an enzyme that in humans is encoded by the ''CYP1B1'' gene. Function CYP1B1 belongs to the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved i ...

, and

CYP2S1 Cytochrome P450 2S1 is a protein that in humans is encoded by the ''CYP2S1'' gene. The gene is located in chromosome 19q13.2 within a cluster including other CYP2 family members such as CYP2A6, CYP2A13, CYP2B6, and CYP2F1. Expression CYP2S1 is ...

to 15-oxo-ETE. *Metabolized in skin epidermis by Epidermis-type lipoxygenase 3 (eLOX3, encoded by the

ALOXE3 Epidermis-type lipoxygenase 3 (ALOXE3 or eLOX3) is a member of the lipoxygenase family of enzymes; in humans, it is encoded by the ''ALOXE3'' gene. This gene is located on chromosome 17 at position 13.1 where it forms a cluster with two other lipo ...

gene) to make two products, hepoxilin A3 (HxA3, i.e., 13''R''-hydroxy-14''S'',15''S''-epoxy-5''Z'',8''Z'',11''Z''-eicosatetraenoic acid) and 15-oxo-ETE). *Converted to its 14,15-

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 ...

derivative, eoxin A4, and further metabolized to eoxin C4, eoxin D4, and eoxin E4 (there is no eoxin B4). *Degraded non-enzymatically to various cell-injuring

electrophile In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carrie ...

s such as 4-hydroxy-2(''E'')-nonenal and 4-oxo-2(''E'')-nonenal. 15(''S'')-HETE may be: *

Oxidized Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a ...

to its keto analog, 15-oxo-ETE, by the same enzyme that converts

of the A, E, and F series to their 15-keto analogs viz., NAD⁺-dependent

15-hydroxyprostaglandin dehydrogenase 15-hydroxyprostaglandin dehydrogenase may refer to: * 15-hydroxyprostaglandin-D dehydrogenase (NADP+) * 15-hydroxyprostaglandin-I dehydrogenase (NADP+) * 15-hydroxyprostaglandin dehydrogenase (NAD+) * 15-hydroxyprostaglandin dehydrogenase (NADP+) ...

; 15-oxo-ETE, similar to 15(S)-HETE, may be acylated into membrane phosphatidylethanolamaine or, similar to 15(''S'')-HpETE, conjugated with

to form a 13-cysteinyl-glycyl-glutamine adduct viz., 13-glutatione,15-oxo-5(''S''),8(''Z''),11(''E'')-eicosatrienoic acid; the latter metabolite is attacked by γ-glutamyl-transferase to form 13-cysteinyl-glycine,15-oxo-5(''S''),8(''Z''),11(''E'')-eicosatrienoic acid. *Acylated into membrane phospholipids, particularly

phosphatidylinositol Phosphatidylinositol (or Inositol Phospholipid) consists of a family of lipids as illustrated on the right, where red is x, blue is y, and black is z, in the context of independent variation, a class of the phosphatidylglycerides. In such molecul ...

and

. Phospholipid products contain this 15(''S'')-HETE most likely at the ''sn''-2 position. 15(''S'')-HETE-containing-phospholipids may also be made directly by the action of 15-LO-1 on membrane phosphatidylinositols or phosphatidylethanolamines containing arachidonic acid at the ''sn''-2 positions. The phosphatidylethanolamine-bound 15-HETE may be converted to phosphatidylethanolamine-bound 15-oxo-ETE. *Oxygenated by 5-lipoxygenase (

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 ...

to form its 5,6-trans epoxide derivative which may then rearrange to the

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 (LX), LXA₄ (i.e. 5(''S''),6(''R''),15(''S'')-trihydroxy-7''E'',9''E'',11''Z'',13''E''-eicosatetraenoic acid) and LXB₄ (i.e., 5(''S''),14(''R''),15(''S'')-trihydroxy-6''E'',8''Z'',10''E'',12''E''-eicosatetraenoic acid). or to 5''(S''),15(''S'')-dihydroperoxy-6''E'',8''Z'',11''Z'',13''E''-eicosatetraenoate (i.e., (5(S),15(S)-diHETE). 5(S),15(S)-diHETE may then be oxidized to 5-oxo-15(''S'')-hydroxy-6''E'',8''Z'',11''Z'',13''E''-eicosatetraenoate (i.e., 5-oxo-15(''S'')-hydroxy-ETE). The latter two metabolites may also be made by 15-LO's metabolism of 5-hydroxyeicosatetraenoic acid (i.e. 5-HETE) and 5-oxo-eicosatetraenoic acid) (i.e. 5-oxo-ETE), respectively. 15(''R'')-HpETE may be: *Reduced to 15(''R'')-HETE by the same pathway that reduces 5(''S'')-HpETE to 15(''S'')-HETE. *Similar to 15(''S'')-HpETE, subject to decomposition to form various bifuctional potentially toxic electrophiles such as 4-hydroxy-2(''E'')-nonenal and 4-oxo-2(''E'')-nonenal. 15(''R'')-HETE may be: *Similar to 15(''S'')-HETE, oxidized by NAD-dependent 5-hydroxyprostaglandin dehydrogenase to form 15-oxo-ETE which product can be converted its 13-cysteinyl-glycyl-glutamyl and then 13-cysteinyl-glycine products as described above for 5(''S'')-HETE. *Similar to 15(''S'')-HETE, oxygenated by ALOX5 to form its 5,6-oxido derivative which then rearranges to the 15(''R'')

diastereomers In stereochemistry, diastereomers (sometimes called diastereoisomers) are a type of stereoisomer. Diastereomers are defined as non-mirror image, non-identical stereoisomers. Hence, they occur when two or more stereoisomers of a compound have di ...

of LXA₄ and (LXB₄ viz., 15-epic LXA₄ 5(''S''),6(''R''),15(''R'')-trihydroxy-7''E'',9''E'',11''Z'',13''E''-eicosatetraenoic acid) and 15-epi-LXB₄ (i.e., 5(''S''),14(''R''),15(''S'')-trihydroxy-''6''E,8''Z'',10''E'',12''E''-eicosatetraenoic acid, respectively.

Activities

15(''S'')-HpETE and 15(''S'')-HETE

Most studies have analyzed the action of 15(''S'')-HETE but not that of its less stable precursor 15(''S'')-HpETE. Since this precursor is rapidly converted to 15(''S'')-HETE in cells, it is likely that the two metabolites share similar activities. In many studies, however, is not clear that these activities reflect their intrinsic action or reflect their conversion to the metabolites sited above. 15(''S'')-HpETE and 15(''S'')-HETE bind to and activate the

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 ...

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 ...

, i.e. BLT2. This receptor activation may mediate, at least in part, certain cell-stimulating activities of the two metabolites. BLT2 may be responsible in part or whole for mediating the growth-promoting and anti- apoptosis (i.e. anti-cell death) activities of 15(S)-HETE in cultured human breast cancer cells; human cancer colon cells, human hepatocellular HepG2 and SMMC7721 cancer cells; mouse

3T3 cells 3T3 cells are several cell lines of mouse embryonic fibroblasts. The original 3T3 cell line (3T3-Swiss albino) was established in 1962 by two scientists then at the Department of Pathology in the New York University School of Medicine, George Tod ...

(a fibroblast cell line); rat PA adventitia fibroblasts; Baby hamster kidney cells; and diverse types of 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 ...

. These growth-stimulating effects could contribute to the progression of the cited cancer types in animal models or even humans and the excess

fibrosis Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...

that causes the narrowing of pulmonary arteries in hypoxia-induced pulmonary hypertension or narrowing of portal arteries in the portal hypertension accompanying liver cirrhosis. 15(''S'')-HETE may also act through BLT2 to stimulate an immediate contractile response in rat pulmonary arteries and its

angiogenic Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splittin ...

effect on human umbilical and dermal vascular endothelial cells. 15(''S'')-HpETE and 15(''S'')-HETE also directly bind with 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 tran ...

. This activation may contribute to the ability of 15(S)-HETE to inhibit the growth of cultured human prostate cancer

PC-3 PC3 (PC-3) is a human prostate cancer cell line used in prostate cancer research and drug development. PC3 cells are useful in investigating biochemical changes in advanced prostate cancer cells and in assessing their response to chemotherapeutic ...

LNCaP LNCaP cells are a cell line of human cells commonly used in the field of oncology. LNCaP cells are androgen-sensitive human prostate adenocarcinoma cells derived from the left supraclavicular lymph node metastasis from a 50-year-old caucasian ma ...

, and

DU145 DU145 (DU-145) is a human prostate cancer cell line. DU145, PC3, and LNCaP are considered to be the standard prostate cancer cell lines used in therapeutic research. The DU145 cell line was derived from a central nervous system metastasis, of pri ...

cell lines and non-malignant human prostate cells; lung adenocarcinoma

A549 cell A549 cells are adenocarcinomic human alveolar basal epithelial cells, and constitute a cell line that was first developed in 1972 by D. J. Giard, et al. through the removal and culturing of cancerous lung tissue in the explanted tumor of a 58- ...

s; human colorectal cancer cells; corneal epithelial cells; and

Jurkat Jurkat cells are an immortalized line of human T lymphocyte cells that are used to study acute T cell leukemia, T cell signaling, and the expression of various chemokine receptors susceptible to viral entry, particularly HIV. Jurkat cells can prod ...

T-cell leukemia cells. The decline in the level of 15(''S'')-HpETE-forming enzymes and consequential fall in cellular 15-HETE production that occurs in human prostate cancer cells may be one mechanism by which this and perhaps other human cancer cells (e.g. those of the colon, rectum, and lung) avoid the apoptosis-inducing actions of 15(''S'')-HpETE and/or 15(''S'')-HETE and thereby proliferate and spread. In this scenario, 15(S)-HETE and one of its formaing enzymes, particularly 15-LOX-2, appear to act as tumor suppressors. Some of the inhibitory effects of 15(''S'')-HpETE and 15(''S'')-HETE, particularly when induced by high concentrations (e.g. >1-10 micromolar), may be due to a less specific mechanism: 15(''S'')-HpETE and to a lesser extent 15(''S'')-HETE induce the generation of

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 ...

. These species trigger cells to activate their death programs, i.e. apoptosis, and/or are openly toxic to the cells. 15(''S'')-HpETE and 15(S)-HETE inhibit angiogenesis and the growth of cultured human chronic myelogenous leukemia K-562 cells by a mechanism that is associated with the production of reactive oxygen species. Several bifunctional electrophilic breakdown products of 15(''S'')-HpETE, e.g. 4-hydroxy-2(''E'')-nonenal, 4-hydroperoxy-2(''E'')-nonenal, 4-oxo-2(''E'')-nonenal, and ''cis''-4,5-epoxy-2(''E'')-decanal, are

mutagens In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer i ...

in mammalian cells and thereby may contripute to the development and/or progression of human cancers.

15(''R'')-HETE

Similar to 15(''S'')-HpETE and 15(''S'')-HETE and with similar potency, 15(''R'')-HETE binds with and activates peroxisome proliferator-activated receptor gamma. The precursor of 15(''R'')-HETE, 15(''R'')-HpETE may, similar to 15(''S'')-HpETE, break down to the mutagenic products 4-hydroxy-2(''E'')-nonenal, 4-hydroperoxy-2(''E'')-nonenal, 4-oxo-2(''E'')-nonenal, and ''cis''-4,5-epoxy-2(''E'')-decanal and therefore be involved in cancer development and/or progression.

15-oxo-ETE

In cultured human monocytes of the

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 ...

, 15-oxo-ETE inactivates IKKβ (also known as

IKK2 IKK-β also known as inhibitor of nuclear factor kappa-B kinase subunit beta is a protein that in humans is encoded by the ''IKBKB'' (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta) gene. Function IKK-β is an enzy ...

) thereby blocking this cell's

NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...

-mediated pro-inflammatory responses (e.g.,.

Lipopolysaccharide Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer ...

-induced production of TNFα,

Interleukin 6 Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene. In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smooth ...

, and

IL1B Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...

) while concurrently activating anti-oxidant responses upregulated through the anti-oxidant response element (ARE) by forcing cytosolic

KEAP1 Kelch-like ECH-associated protein 1 is a protein that in humans is encoded by the ''Keap1'' gene. Structure Keap1 has four discrete protein domains. The N-terminal Broad complex, Tramtrack and Bric-à-Brac (BTB) domain contains the Cys151 res ...

to release

NFE2L2 Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the ''NFE2L2'' gene. NRF2 is a basic leucine zipper (bZIP) protein that may regul ...

which then moves to the nucleus, binds ARE, and induces production of, e.g. hemoxygenase-1, NADPH-quinone oxidoreductase, and possibly glutamate-cysteine ligase modifier. By these actions, 15-oxo-ETE may dampen inflammatory and/or

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 ...

responses. In a cell-free system, 15-oxo-ETE is a moderately potent (IC₅₀=1 μM) inhibitor of

12-lipoxygenase ALOX12 (), also known as arachidonate 12-lipoxygenase, 12-lipoxygenase, 12''S''-Lipoxygenase, 12-LOX, and 12''S''-LOX is a lipoxygenase-type enzyme that in humans is encoded by the ''ALOX12'' gene which is located along with other lipoyxgenases on ...

but not other human lipoxygenases. This effect could also have anti-inflammatory and anti-oxidative effects by blocking the formation of 12-HETE and

s. 15-Oxo-ETE is an example of an α,β unsaturated ketone

Electrophile In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carrie ...

. These ketones are highly reactive with nucleophiles, adducting to, for example, the cysteines in transcription and transcription-related regulatory factors and enzymes to form their alkylated and thereby often inactivated products. It is presumed that the preceding activities of 15-oxo-ETE reflect its adduction to the indicated elements. 15-Oxo-ETE, at 2-10 μM, also inhibits the proliferation 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 LoVo human colorectal cancer cells and at the extremely high concentration of 100 μM inhibits the proliferation of cultured MBA-MD-231 and MCF7 breast cancer cells as well as SKOV3 ovarian cancer cells. They may use a similar "protein-adduction" mechanism; if so the target protein(s) for these effects have not been defined or even suggested. This 15-oxo-ETE action may prove to inhibit the remodeling of blood vessels and reduce the growth of the cited cell types and cancers. At sub-micromolar concentrations, 15-oxo-ETE has weak Chemotaxis activity for human

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 ...

s and could serve to recruit this White blood cell into

inflammatory response Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecu ...

5-Oxo-15(S)-hydroxy-ETE

5-Oxo-15(S)-hydroxy-ETE is properly a member of the 5-HETE family of agonists which binds to the

Oxoeicosanoid receptor 1 Oxoeicosanoid receptor 1 (OXER1) also known as G-protein coupled receptor 170 (GPR170) is a protein that in humans is encoded by the OXER1 gene located on human chromosome 2p21; it is the principal receptor for the 5-Hydroxyicosatetraenoic acid fa ...

, a

, to activate its various target cells. As such, it is a potent stimulator of

leukocytes White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...

, particularly

eosinophils 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 ...

, as well as other OXE1-bearing cells including

MDA-MB-231 Scientists study the behaviour of isolated cells grown in the laboratory for insights into how cells function in the body in health and disease. Experiments using cell culture Cell culture or tissue culture is the process by which cells are ...

MCF7 MCF-7 is a breast cancer cell line isolated in 1970 from a 69-year-old White woman. MCF-7 is the acronym of Michigan Cancer Foundation-7, referring to the institute in Detroit where the cell line was established in 1973 by Herbert Soule and co-wor ...

, and SKOV3 cancer cells (see 5-Hydroxyicosatetraenoic acid and 5-oxo-eicosatetraenoic acid). It also binds with and activates

PPARγ 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 thereby can stimulate or inhibit cells independently of OXE1.

Lipoxins

LXA4, LXB4, AT-LXA4, and AT-LXB4 are

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 ...

, i.e. they potently inhibit the progression and contribute to the resolution of diverse inflammatory and allergic reactions (see specialized proresolving mediators#lipoxins 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).

Eoxins

Eoxin A4 Eoxin A4, also known as 14,15-leukotriene A4, is an eoxin. Cells make eoxins by metabolizing arachidonic acid with a 15-lipoxygenase enzyme to form 15(''S'')-hydroperoxyeicosapentaenoic acid (i.e. 15(''S'')-HpETE). This product is then converted ...

Eoxin C4 Eoxin C4, also known as 14,15-leukotriene C4, is an eoxin. Cells make eoxins by metabolizing arachidonic acid with a 15-lipoxygenase enzyme to form 15(''S'')-hydroperoxyeicosapentaenoic acid (i.e. 15(''S'')-HpETE). This product is then converted ...

Eoxin D4 Eoxin D4, also known as 14,15-leukotriene D4, is an eoxin. Cells make eoxins by metabolizing arachidonic acid with a 15-lipoxygenase enzyme to form 15(''S'')-hydroperoxyeicosapentaenoic acid (i.e. 15(''S'')-HpETE). This product is then converted ...

, and

Eoxin E4 Eoxin E4, also known as 14,15-leukotriene E4, is an eoxin. Cells make eoxins by metabolizing arachidonic acid with a 15-lipoxygenase enzyme to form 15(''S'')-hydroperoxyeicosapentaenoic acid (i.e. 15(''S'')-HpETE). This product is then converted ...

and analogs of

leukotriene A4 Leukotriene A4 (LTA4) is a leukotriene, and is the precursor for the productions of LTB4 (leukotriene B)) and LTC4 (leukotriene C4). Biosynthesis of Leukotriene A4 Following the biosynthesis of eicosanoid, triggered as a result of infection or ...

, C4,

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 by bas ...

, and E4. Formation of the leukotrienes is initiated by 5-lipoxygenase metabolism of arachidonic acid to form a 5,6-

viz, leukotriene A4; the latter metabolite is then converted to C4, D4, and E4 in succession. Formation of the eoxins is initiated by a 15-lipoxyenase-mediated metabolism of arachiconic acid to a 14,15-epoxide, eoxin A4 followed by its serial conversion to epoxins C4, D4, and E4 using the same pathways and enzymes that metabolize leukotriene A4 to its down-stream products. Preliminary studies have found that the eoxins have pro-inflammatory actions, suggest that they are involved in severe asthma, aspirin-induced asthma attacks, and perhaps other allergic reactions. The production of eoxins by Reed-Sternburg cells has also led to suggestion that they are involve in the lymphoma of Hodgkins disease. Drugs blocking the 15-lipoxygenases may be useful for inhibiting inflammation by reducing the production of the eoxins.

References

External links

15-LOX Gene Atlas entry

15-LOX BRENDA homo sapiens entry
{{DEFAULTSORT:Hydroxyeicosatetraenoic acid, 15- Fatty acids Eicosanoids Cell biology Immunology

Nomenclature and stereoisomers

Production

Further metabolism

Activities

15(''S'')-HpETE and 15(''S'')-HETE

15(''R'')-HETE

15-oxo-ETE

5-Oxo-15(S)-hydroxy-ETE

Lipoxins

Eoxins

See also

References

External links