Poxytrin
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Poxytrins or dihydroxy-''E'',''Z'',''E''-polyunsaturated fatty acids (dihydroxy-''E'',''Z'',''E''-PUFAs) are
PUFA 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 ...
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
s that possess two
hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
residues and three in-series
conjugated double bond In physical organic chemistry, a conjugated system is a system of connected p-orbitals with delocalized electrons in a molecule, which in general lowers the overall energy of the molecule and increases stability. It is conventionally represent ...
s in an ''E'',''Z'',''E'' cis–trans configuration. Poxytrins have
platelet Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...
-inhibiting properties that are not found in isomers with three conjugated double bonds presenting in a different geometry. The unique ''E'',''Z'',''E'' configuration in poxytrins may prove to be relevant in treating human conditions and diseases that involve pathological platelet activation.


Types

Poxytrins are metabolites of
docosahexaenoic acid Docosahexaenoic acid (DHA) is an omega−3 fatty acid that is an important component of the human brain, cerebral cortex, skin, and retina. It is given the fatty acid notation 22:6(''n''−3). It can be synthesized from alpha-linolenic acid or ...
(DHA),
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 ...
(AA), and
α-linolenic acid α-Linolenic acid, also known as ''alpha''-linolenic acid (ALA) (from Greek ''alpha'' denoting "first" and ''linon'' meaning flax), is an ''n''−3, or omega-3, essential fatty acid. ALA is found in many seeds and oils, including flaxseed, ...
(ALA). Poxytrins derived from AA are termed linotrins.


PDX

Protectin DX (PDX) is perhaps the most prominent poxytrin. It is not to be confused with its isomer
protectin D1 Protectin D1 also known as neuroprotectin D1 (when it acts in the nervous system) and abbreviated most commonly as PD1 or NPD1 is a member of the class of specialized proresolving mediators. Like other members of this class of polyunsaturated fat ...
(PD1). PD1 is structurally identical to PDX except that its three conjugated double bonds 11''E'',13''E'',15''Z'' have the ''E'',''E'',''Z'' configuration. PDX and PD1 both possess potent specialized pro-resolving mediator (SPM) anti-inflammatory activity, but only PDX inhibits human platelet aggregation responses. PDX's anti-platelet activity is shared with various other dihydroxy-''E'',''Z'',''E''-PUFAs, but not with dihydroxy-PUFAs that have an ''E'',''E'',''E'' or ''E'',''E'',''Z'' configuration. Cells make PDX by metabolizing DHA by double oxygenation with a 15-lipoxygenase to form the 10''R'',17''S''-hydroxperoxy intermediate which is reduced to its 10''R'',17''S''-hydroxyl product, PDX, probably by cytosolic glutathione peroxidase 1 (GPX1). Serial metabolism by two different lipoxygenases or by a lipoxygenase and a cytochrome P45 on a 1''Z'',4''Z'',7''Z''-PUFA may also make a 1,7-dihydroxy 2''E'',4''Z'',6''E'' product.


Other poxytrins

* 10''R'',17''S''-diHDHA is the 10''R''
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 ...
of PDX, with the 10''R'' hydroxyl residue being formed by
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
COX-2 Cyclooxygenase-2 (COX-2), also known as prostaglandin-endoperoxide synthase 2 ( HUGO PTGS2), is an enzyme that in humans is encoded by the ''PTGS2'' gene. In humans it is one of three cyclooxygenases. It is involved in the conversion of arachid ...
or a cytochrome P450. * 8''S'',15''S''-diHETE has been observed in guinea pig tissues, probably made through double oxygenation of AA by a 15-lipoxygenase (probably
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 ...
) or serial metabolism by two enzymes. * 10''S'',17''S''-diHDHA is the 13''Z'' cis–trans isomer of 10-epi-protectin D (which has a 13''E'' double bond instead). 10''S'',17''S''-diHDHA is formed in vitro by stimulated human leukocytes and possesses SPM anti-inflammatory activity. * 7-epi-MaR1 is a maresin isomer1, and likewise possesses SPM activity.


Linotrins

Linotrin-1 and linotrin-2 are among the four isomeric metabolites produced by incubating ALA with
ALOX15B Arachidonate 15-lipoxygenase type II is an enzyme that in humans is encoded by the ''ALOX15B'' gene. ALOX15B, also known as 15-lipoxygenase-2 (15-LO-2 or 15-LOX-2), is distinguished from its related oxygenase, ALOX15 or 15-lipoxygenase-1. Funct ...
. The extent to which the linotrins form in cells or in vitro is not clear.


Activity

Stimulating agents such as collagen depend on platelets to make and release thromboxane A2 (TXA2) to mediate and/or enhance their aggregating activity. 10''R'',17''S''-diHDHA, and PDX to a slightly lesser degree, inhibit the human platelet aggregation response to collagen at ≥ 100–200
nanomolar Molar concentration (also called molarity, amount concentration or substance concentration) is the number of moles of solute per liter of solution. Specifically, It is a measure of the concentration of a chemical species, in particular, of a so ...
concentrations. This appears to reflect the ability of poxytrins to inhibit the activities of
COX-1 Cyclooxygenase 1 (COX-1), also known as prostaglandin-endoperoxide synthase 1 ( HUGO PTGS1), is an enzyme that in humans is encoded by the ''PTGS1'' gene. In humans it is one of three cyclooxygenases. History Cyclooxygenase (COX) is the centr ...
and
COX-2 Cyclooxygenase-2 (COX-2), also known as prostaglandin-endoperoxide synthase 2 ( HUGO PTGS2), is an enzyme that in humans is encoded by the ''PTGS2'' gene. In humans it is one of three cyclooxygenases. It is involved in the conversion of arachid ...
, thereby blocking the production of TXA2 and thus interfering with the activation of the
thromboxane receptor The thromboxane receptor (TP) also known as the prostanoid TP receptor is a protein that in humans is encoded by the ''TBXA2R'' gene, The thromboxane receptor is one among the five classes of prostaglandin receptor, prostanoid receptors and was ...
by TXA2. The linotrins appear to use a similar mechanism, and to have similar or slightly lower potencies. However, the linotrins are 20- to 100-fold stronger in inhibiting human platelet aggregation compared to 5-HETE and 12-HETE, two mono-hydroxyl-containing
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 ...
s that contain an ''E,Z'' conjugated double bond configuration. Other biologically-active poxytrins have yet to be tested for, but are projected to possess anti-platelet activity.


References

{{Reflist, 30em Cell biology Cell communication Cell signaling Immunology Fatty acids