Docosahexaenoic acid (DHA): structure, metabolism, and benefits

Docosahexaenoic acid or DHA is a polyunsaturated fatty acid (PUFA) with 22 carbon atoms and six double bonds in the cis (Z) configuration.
Since the first double bond, with respect to the methyl end, is between is between carbon 3 and 4, it is an omega-3 polyunsaturated fatty acid. In shorthand notation, it is referred to as 22:6n-3.
DHA, like other fatty acids such as arachidonic acid and eicosapentaenoic acid or EPA, also belongs to the group of very long chain fatty acids or VLCFAs, i.e., fatty acids with 20 carbon atoms or more.

Molecular weight: 328.496 g/mol
Molecular formula: C22H32O2
Boiling point‎: not available
Melting point‎: ‎-44 °C (-47 °F; 229 K)
IUPAC name: (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid
CAS registry number: 6217-54-5
PubChem: 445580


Other names
Cervonic acid
cis-4,7,10,13,16,19-Docosahexaenoic acid
Docosahexaenoic acid (all-Z)
Docosahexaenoic Acid (All-Z Isomer)
Docosahexaenoic Acid, 4,7,10,13,16,19-(All-Z-Isomer)(4Z,7Z,10Z,13Z,16Z,19Z)-Docosahexaenoic acid


Docosahexaenoic acid metabolism

Docosahexaenoic acid is, among unsaturated fatty acids present in human tissues in substantial amount, the extreme example, being the most unsaturated and longest one.
In most membranes, it is preferentially accumulated in the two major structural phospholipids, i.e., phosphatidylethanolamine, and, in lesser amount, phosphatidylcholine. However, this “rule” does not apply to all cells. For example, in the membranes of neurons, high DHA concentrations are found in phosphatidylserine, a non-structural phospholipid.
Within membrane phospholipids, DHA is located, like the other PUFAs, mainly in the sn-2 position, while sn-1 position is mainly occupied by saturated fatty acids, in particular stearic acid and palmitic acid.
Docosahexaenoic acid can originate from:

  • diet, as preformed product;
  • de novo.

De novo synthesis of docosahexaenoic acid

DHA, like arachidonic acid, can only be synthesized from dietary precursors. Below, the metabolic pathway for its synthesis from α-linolenic acid, an essential fatty acid, through a series of seven steps is analyzed. In this metabolic pathway, we shall meet the other possible precursors.
The first six steps, a series of elongation and desaturation reactions, occur in the endoplasmic reticulum while the last one, a β-oxidation, in peroxisomes.

  • In the first step, α-linolenic acid is desaturated to form stearidonic acid (18:4n-3), in a reaction catalyzed by Δ6-desaturase, also referred to as acyl-CoA 6-desaturase (EC The enzyme requires the presence of zinc, magnesium and pyridoxine as cofactors.
  • In the second step, stearidonic acid is elongated to form eicosatetraenoic acid (20:4n-3), in a reaction catalyzed by elongase 5 (EC, as well as the other elongases from 1 to 7).
  • Eicosatetraenoic acid is desaturated to form eicosapentaenoic acid, in a reaction catalyzed by Δ5-desaturase (E.C.
  • EPA is then elongated to form n-3 docosapentaenoic acid or DPA (22:5n-3), in a reaction catalyzed by elongase 5 and/or elongase 2 (it is still unclear if one or both the aforementioned elongases catalyze this step).
  • DPA is elongated to form n-3 tetracosapentaenoic acid (24:5n-3), in a reaction catalyzed by elongase 2.
  • n-3 Tetracosapentaenoic acid is desaturated to form n-3 tetracosahexaenoic acid (24:6n-3), in a reaction catalyzed by Δ6-desaturase.
  • Finally, n-3 tetracosahexaenoic acid leaves the endoplasmic reticulum and is transferred to peroxisomes where it is converted to docosahexaenoic acid through removal of a two carbon chain by β-oxidation.
Synthesis of DHA

Then, DHA leaves peroxisomes and returns to the endoplasmic reticulum where it is incorporated into membrane phospholipids.
In humans, conversion of α-linolenic acid to DHA seems to be very low, ranging from 0% to 4%. However, higher values, up to 9%, have been found in young women, perhaps related to the effects of estrogen on Δ6-desaturase.

Note: a Δ4-desaturase, that allows the synthesis of docosahexaenoic acid directly from 22:5n-3, was identified in some marine microalgae, such as those belonging to the genera Pavlova and Isochrysis, in a lower eukaryote, the marine microheterotroph Thraustochyrium sp., and in a marine, herbivorous, teleost fish: Siganus canaliculatus.

Regulation of docosahexaenoic acid synthesis

De novo synthesis of docosahexaenoic acid is influenced by factors that act on the catalytic activity of some of the enzymes involved, and by the competition that occurs between PUFAs for the same desaturases and elongases.


The enzyme catalyzes both the oxidation of α-linolenic acid to stearidonic acid, the rate-limiting step of this metabolic pathway, and of 24:5n-3 to 24:6n-3, the most direct precursor of DHA (see Fig. 3).
Δ6-desaturase, like Δ5-desaturase, is inhibited by cholesterol, saturated and trans fatty acids, alcohol, glucocorticoids, and adrenaline. And their activity is also reduced in diabetes mellitus, hyperlipidemia, hypertension, and metabolic syndrome.
Protein deficiency and total fasting also reduce the activity of Δ6-desaturase, while its activity is enhanced by partial caloric restriction and insulin.
Finally, the competition between α-linolenic acid and 24:5n-3 for the desaturase could explain the decrease in DHA levels observed as a result of α-linolenic acid supplementation after certain intakes.

It should be undescored that, in humans, the activities of Δ5 and Δ6 desaturases are slow, with Δ5-desaturase > Δ6-desaturase. Therefore, the conversion of α-linolenic acid and linoleic acid to their respective metabolites may be inadequate to the needs under certain conditions, such as in ageing subjects and some diseases.

Elongase 2

The second elongation reaction catalyzed by elongase 2, from DPA to 24:5n-3 (see Fig. 3), seems to be saturated when α-linolenic acid, stearidonic acid or EPA are supplied in the diet, suggesting that elongase 2 might play a crucial role in understanding if the synthesis of docosahexaenoic acid can be increased by dietary means.

Competition between omega-3, omega-6 and omega-9 fatty acids

α-Linolenic acid, linoleic acid and oleic acid are metabolized by the same set of desaturases, Δ5 and Δ6 desaturases, and elongases, elongases 2 and 5. Therefore, the three series of derived PUFAs, omega-3,  and omega-9, compete for the same set of enzymes. However, it seems that substrates preferentially metabolized are omega-3 rather than omega-6 polyunsaturated-fatty acids, and omega-6 rather than omega-9, therefore with a sequence of preference: omega-3 > omega-6 > omega-9.
It should be emphasized, however, that linoleic acid is much more abundant than α-linolenic acid in the Western diet, as well as in human tissues.

Note: under physiological conditions, the metabolites of omega-9 are present in trivial amounts. This is of great importance because if high amounts of 20:3n-9 are found, there is a deficiency of omega-3 and omega-6, that is, a deficiency of essential fatty acids.

Sites of biosynthesis of docosahexaenoic acid

The main site for the synthesis of DHA is the liver. The synthesized molecule, after its secretion into the bloodstream, becomes available for uptake by other organs, such as the brain. Among neural cells, namely neurons, astrocytes, oligodendrocytes, and microglia, only astrocytes can synthesize DHA, whereas neurons, which are the major site for its accumulation (see next paragraph), can’t synthesized it, lacking desaturase activity.
In astrocytes, the availability of the preformed docosahexaenoic acid negatively influences de novo synthesis of the molecule. Hence, their biosynthetic activity is a quantitatively minor source for DHA accretion in the brain when the circulating supply of the molecule is adequate.
Finally, it should be noted that brain cerebro-microvascular endothelial cells, although capable to elongate and desaturate shorter chain fatty acids (up to 18 C atoms), lack the capacity to catalyze the final desaturation step in the synthesis of both DHA and 22:5n-6.

Tissue distribution of DHA

DHA is not homogeneously distributed in tissues and cells, and, based on the amounts present, it is possible to identify two tissue classes: high-DHA tissues and low-DHA tissues.

  • Some cells and tissues contain high amounts of the fatty acid, often up to almost 50% of the moles of all acyl chains. Examples are neurons, sperm, and the rod outer segment. These cells contain so much docosahexaenoic acid that, in their membranes, phospholipids with the fatty acid both in sn-1 and sn-2 position are common. And it should be underscored that, in these cells, DHA levels are not affected by diet.
    DHA is the most abundant polyunsaturated fatty acid in the brain, and numerous studies point out that such levels are essential for optimal function of neurons and retina. And docosahexaenoic acid accretion in the central nervous system occurs during the developmental stage, mainly due to the molecule derived from biosynthesis in the liver or from diet. However, as previously seen, DHA can also be synthesized in the astrocytes.
  • Other tissues and cells normally contain low amounts of the fatty acid, less than a few mol% of all acyl chains. In these sites docosahexaenoic acid is present primarily in the sn-2 position of the phospholipids, since it is not present in sufficient amounts to promote esterification in sn-1 position.
    And, unlike the previous bullet point, in this tissues, DHA levels can be affected by diet. Therefore, it is likely that the health benefits associated with intake of the molecule originate from these tissues.

Metabolites of docosahexaenoic acid

The idea that DHA could be beneficial for human health followed the work of Hans Olaf Bang and Jorn Dyerberg, who in the early 70’s of the last century sought the reason why thrombotic diseases, and in particular ischemic heart disease, were so rare among Greenland Eskimos. These authors suggested that such rarity of thrombotic diseases was due to the fish-based diet of these populations, rich in DHA and EPA, both found in good amounts in the blood of these subjects.
These initial observations led to epidemiological studies, cell culture researches, as well as animal and human feeding studies, searching for the link between DHA and EPA levels and human health.
Docosahexaenoic acid has been involved in virtually every human disease. Health benefits have been attributed to cancer treatment, heart disease, neuronal functions, immune problems, aging, but also to other conditions such as sperm fertility, malaria and migraine. So apparently unrelated abnormalities. This suggests that the action of the molecule occurs at a very basic level, common to many cell types.

Mechanisms of action of docosahexaenoic acid: SPMs

DHA can bring health benefits acting in two ways: as such or through its metabolites, of which, currently, over 70 have been described.
In fact, a first molecular explanation was provided for the many health benefits attributed to this fatty acid, as well as to EPA and DPA, different from its direct action. Namely, a new class of potent lipid mediators, termed specialized pro-resolving mediators or SPMs, has been described. Such molecules have been involved in the active resolution of inflammation, reduction of pain, host defense, and protection of the organ from damage caused by ischemia-reperfusion.

Pro-inflammatory Mediators and SPMs

They are synthesized at the site of inflammation or tissue damage through coordinated enzyme-catalyzed reactions, produced in small amounts, some in a specific tissue or cell type, such as Maresins in macrophages (see below), others, whose synthesis involves multiple cell types, that is, a transcellular synthesis occurs.
SPMs are able to strongly regulate the activity of target cells. For example, in the course of inflammation, after their binding to specific cellular receptors, they regulate cytokine and chemokine production, neutrophil infiltration, and the clearance of apoptotic neutrophils by macrophages, thus promoting the return to tissue homeostasis.
SPMs comprise four families of lipid mediators, below summarized.

  • Lipoxins, the first SPMs to be discovered, synthesized from arachidonic acid.
  • Maresins, Protectins and Resolvins, synthesized from EPA, DPA and docosahexaenoic acid, discovered only recently.

Noteworthy, while arachidonic acid is the precursor of both pro-inflammatory lipid mediators, which have been discovered much earlier than SPMs, and proresolving lipid mediators, EPA, DPA and DHA are precursors of cytoprotective, anti-inflammatory and proresolving lipid mediators.
And the synthesis of these mediators occurs with a precise timeline. Indeed, in acute inflammation, it is possible to identify an onset pro-inflammatory phase, characterized by the synthesis of Leukotrienes and Prostaglandins from arachidonic acid, and a second resolution phase, in which Lipoxins, Maresins, Protectins and Resolvins are synthesized.

It should be noted that docosahexaenoic acid can also undergo a free radical-mediated peroxidation leading to the formation of metabolites, such as Neuroprostanes and Neuroketals, that are therefore produced and act virtually anywhere and at various concentrations.

Docosahexaenoic acid and secretory phospholipases A2

Docosahexaenoic acid present at the site of injury can derive from the circulating blood stream or be released by membrane phospholipids of the involved cells.
The amount of DHA present in whole blood of healthy subjects is modest, ranging from 1.3 to 5% of the total fatty acids, variations attributed to differences in dietary intake. The plasma molecule reaches, within a few minutes from initial damage, the site of the lesion, leaves the circulating blood stream and is therefore available for enzymatic conversion to SPMs, which will interact with local immune cells.
The release of DHA from membrane phospholipids is due to the hydrolytic activity of secretory phospholipases A2 or sPLA2, the first enzymes to act in docosahexaenoic acid metabolism.
Similar considerations can be also applied to EPA, DPA and arachidonic acid.
Phospholipases A2 (EC are a family of hydrolases composed, in mammals, of more than 30 enzymes, whose activation occurs in response to specific cell stimuli.
Secretory phospholipases A2 are a subfamily that accounts for about one third of all phospholipases A2 and catalyze the release of PUFAs from membrane phospholipids.

LOX, COX-2, sEH, CYP, GST, GGT and dipeptidases

Below is a brief description of the other most important enzymes involved in DHA metabolism, enzymes that operate a strict stereochemical control.

  • Lipoxygenases
    They are among the main enzymes involved, and catalyze the synthesis of DHA hydroperoxides, or HpDHA, via oxygen insertion in the S configuration. Such enzymes are 5-lipoxygenase or 5-LOX (EC, 12-lipoxygenase or 12-LOX (EC and the 15-lipoxygenase or 15-LOX (EC
    It should be noted that 5-lipoxygenase and 12-lipoxygenase also have an epoxide generating activity.
  • Cyclooxygenase 2
    Cyclooxygenase 2 or COX-2 or prostaglandin-endoperoxide synthase 2, together with COX-1, is one of the two isoforms of cyclooxygenases, enzymes able to catalyze the formation of endoperoxides (EC for COX-1 and COX-2).
    COX-1 and COX-2 activity is influenced by aspirin, which causes an irreversible acetylation of an active-site serine residue.
    Acetylation of COX-1 inhibits its activity, thus inhibiting the synthesis of thromboxanes and prostaglandins in the cells where these biosynthesis pathways occur.
    Conversely, acetylation of COX-2 does not destroy the enzymatic activity. The enzyme loses cyclooxygenase activity but acquires an enzymatic activity similar to that of 15-lipoxygenase. In fact, the acetylated enzyme catalyzes, like cytochrome P450 (see below), oxygen insertion at position 17, as is the case with 15-LOX, but with opposite stereochemistry, i.e., R- rather than S configuration. Therefore, the product of the reaction is 17R-hydroperoxide-DHA and not 17S-hydroperoxide-DHA (see below).
  • Soluble epoxide hydrolase
    This enzyme (EC, abbreviated as sEH, in mammals, is able to catalyze hydrolysis of a broad spectrum of epoxides.
  • Cytochrome P450 (H5)
    Several members of the cytochrome P450 superfamily are involved in the metabolism of docosahexaenoic acid. The isoforms of cytochrome P450 families 1 to 3 are mainly epoxygenases, and act also on EPA and arachidonic acid, whereas the isoforms of the family 4 are mainly omega-hydroxylases.
  • Other enzymes involved are some member of glutathione S-transferase family or GSTs (EC, gamma-glutamyl transferase or GGT (EC, and dipeptidases.

Below is a review of the most important members of Maresin, Protectin and D-series Resolvin families.

Docosahexaenoic acid and Maresins

Maresins or macrophage mediators in resolving inflammation, are a family of molecules with analgesic activity, involved in inflammation resolution, and tissue regeneration.
They are produced mainly by macrophages, through different biosynthetic pathways which share the first step: oxygenation of DHA at position 14, in a reaction catalyzed by 12-lipoxygenase. The product of this reaction is the hydroperoxy intermediate 14S-hydroperoxy-DHA or 14S-HpDHA or 14S-hydroperoxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid.

Note: human macrophage 12-lipoxygenase also converts arachidonic acid to the corresponding 14S-hydroperoxide (98%), with an equivalent efficiency to that of DHA conversion to 14S-HpDHA.

Hereafter, some examples of Maresins.

Maresin 1

Maresin 1 or MaR1 or 7R,14S-diHDHA or 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid has a E,E,Z conjugated triene within the six double bonds.

Maresin 1

MaR1 was the first member of this family to be identified, and is the product of a biosynthesis pathway that consists of three steps, the first of which has been analyzed in the previous paragraph.
In the second step, 12-lipoxygenase catalyzes the epoxidation of 14S-HpDHA to 13S,14S-epoxy-maresin or 13S,14S-eMaR, or 13S,14S-epoxy-DHA or 13S,14S-epoxy-4Z,7Z,9E,11E,16Z,19Z- docosahexaenoic acid. This molecule is also a central intermediate in the biosynthesis of Maresin 2 and MCTR1, MCTR3, MCTR3 (see below).
Finally, 13S,14S-eMaR is converted to MaR1 in a hydrolase catalyzed reaction leading to the introduction of a hydroxyl group at position 7 together with a rearrangement of the double bonds.
Maresin 1 is also present in primitive invertebrates, such as Platyhelminthes or flatworms. This suggests that its structure and function have been preserved during evolution.

14S-HpDHA can undergo a second oxygenation catalyzed by 5-lipoxygenase to form 7S,14S-dihydroxy-DHA (E,Z,E), an isomer of MaR1.

Maresin 2

Maresin 2 or MaR2 or 13R,14S-diHDHA or 13R,14S-dihydroxy-4Z,7Z,9E,11E,16Z,19Z-docosahexaenoic acid is synthesized via the 13S,14S-epoxy-maresin intermediate (see above), in a reaction catalyzed by sEH.
Like Maresin-1, it has a conjugated triene, but with Z,E,E structure.

Maresin conjugates in tissue regeneration

13S,14S-Epoxy-maresin can also be converted to Maresin conjugates in tissue regeneration or MCTRs.

Maresin conjugates in tissue regeneration

In the first step of MCTR biosynthesis pathway, 13S,14S-epoxy-MaR reacts with glutathione to form MCTR1 or 13R-glutathion, 14S-HDHA, or 13R-glutathionyl,14S-hydroxy-4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid, in a reaction that can be catalyzed by two enzymes from the glutathione S-transferase family: leukotriene C4 synthase or LTC4S and GSTM4.
In the second step, gamma-glutamyl transferase catalyzes the cleavage of the γ-glutamyl group from MCTR1 to form MCTR2 or 13R-cysteinylglycinyl,14S-HDHA or 13R-cysteinylglycinyl,14S-hydroxy-4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid.
Finally, in a reaction catalyzed by dipeptidases, the cysteinyl-glycinyl bond of MCTR2 is cleaved to form the third member of the family: MCTR3 or 13R-cysteinyl,14S-HDHA or 13R-cysteinyl,14S-hydroxy-4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid.
Like Maresin-2, MCTRs have a Z,E,E conjugated triene.

Maresin-like lipid mediators

Unlike macrophages, platelets and leukocytes produce a group of docosahexaenoic acid derivatives defined as Maresin-like mediators, in particular Maresin-L1 or 14S-22-diHDHA or 14S,22-dihydroxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid, and Maresin-L2 or 14R,22-diHDHa or 14R,22-dihydroxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid.

Maresin L1 and Maresin L2

Below, the biosynthesistic pathways for the two molecules are described.

  • Maresin-L1
    14S-hydroperoxy-DHA is reduced to 14S-HDHA, in a reaction catalyzed by a peroxidase.
    In the next step, 14S-HDHA is oxidized at position 22 to form Maresin-L1, in a reaction catalyzed by enzymes belonging to the cytochrome P450 family.
  • Maresin-L2
    Cytochrome P450 activity can also convert docosahexaenoic acid to 14R-HDHA.
    In the next step, 14R-HDHA is hydroxylated at position 22 to form Maresin-L2, again, in a reaction catalyzed by cytochrome P450.

Finally, 14S-HDHA and 14R-HDHA can undergo an alternative n-1 oxidation by cytochrome P450 to form respectively 14S,21S-diHDHA, 14S,21R-diHDHA, 14R,21S-diHDHA, and 14R,21R-diHDHA.
Cytochrome P450 activity on 14S-HDHA also leads to the formation of 14S,20R-diHDHA.

Docosahexaenoic acid and Protectins

They were discovered in studies on metabolism of docosahexaenoic in brain tissue in response to aspirin treatment, and initially termed Neuroprotectins. Indeed, their production, like their action, is not restricted to neural tissue, so the term “Protectins” was preferred.
They are molecules that, like docosahexaenoic acid, have six double bonds. And, like Leukotrienes and several Maresins, three of these double bonds are conjugated, respectively, those at positions 11, 13 and 15, that is, there is a conjugated triene.
Another distinctive feature is the hydroxyl group at position 17, shared with Resolvins (see below).
Their molecular structures are highly conserved from fish to humans.
Hereafter, some examples of Protectins.

Protectin D1

The most famous member of this family is Protectin D1 or PD1, or 10R,17S-diHDHA, or 10R,17S-dihydroxy-4Z,7Z,11E,13E,15Z,19Z-docosahexaenoic acid.

It is the final product of a biosynthesis pathway that consists of three steps.
In the first step, the oxygenation of DHA at position 17 occurs, to form 17S-hydroperoxy-DHA or 17S-HpDHA, or 17S-hydroperoxy-4Z,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid (see fig. 10). The reaction is catalyzed by 15-lipoxygenase and is shared with D-series Resolvin biosynthesis (see below).
In the second step, 17S-HpDHA is epoxidated enzymatically to 16S,17S-epoxy-DHA or 16S,17S-epoxy-4Z,7Z,10Z, 12E,14E,19Z-docosahexaenoic acid.
Finally, the hydrolysis of 16S,17S-epoxy-DHA leads to PD1 formation. The reaction is catalyzed by sEH, with the formation of the correct double bond geometry, i.e. cis, trans, trans (11E,13E,15Z).

Protectin conjugates in tissue regeneration

As seen for Maresins, and below for D-series Resolvins, Protectins can react with glutathione to form a family of molecules called Protectin conjugates in tissue regeneration or PCTRs.

Protectin Conjugates in Tissue Regeneration

In the first step of PCTR biosynthesis pathway, 16S,17S-epoxy-DHA reacts with glutathione to form PCTR1 or 16R-glutathionyl-17S-HDHA or 16R-glutathionyl,17S-hydroxy-4Z,7Z,10Z,12E,14E,19Z-docosahexaenoic acid, in a reaction catalyzed by GST.
In the second step, gamma-glutamyl transferase catalyzes the cleavage of the γ-glutamyl group from PCTR1 to form PCTR2 or 16R-cysteinylglycinyl,17S-HDHA or 16R-cysteinylglycinyl,17S-hydroxy-4Z,7Z,10Z,12Z,14E,19Z-docosahexaenoic acid.
Finally, in a reaction catalyzed by dipeptidases, the cysteinyl-glycinyl bond of PCTR2 is cleaved to form the last member of the family: PCTR3 or 16R-cysteinyl,17S-HDHA or 16R-cysteinyl,17S-hydroxy-4Z,7Z,10Z,12Z,14E,19Z-docosahexaenoic acid.

Protectin X

Protectin X or PDX or 10S,17S-dihydroxy-DHA or 10S,17S-diHDHA or 10S,17S-dihydroxy-4Z,7Z,11E,13Z,15E,19Z-docosahexaenoic acid is an isomer of PD1. The two molecules differ in the:

  • configuration of carbon 10: R in PD1 and S in PDX;
  • geometry of the conjugated double bonds: E,E,Z for PD1 and E,Z,E for PDX.

The synthesis pathway for PDX consists of several steps and has in common with PD1 the synthesis of the intermediate 17S-hydroperoxy-DHA.
Then, 17S-hydroperoxy-DHA, in a double di-oxygenation reaction, is converted to PDX. This reaction is catalyzed by 5-lipoxygenase.
Note: PDX is less active than PD1.

Furthermore, 16S,17S-epoxy-DHA can undergo non-enzymatic hydrolysis to form a racemic mixture of two minor products, 16R/S,17S-diHDHA and 10R/S,17S-diHDHA.

Aspirin and Protectins

An additional pathway for the synthesis of Protectins occurs in response to aspirin treatment, that is, acetylsalicylic acid, and to its effect on COX-2 catalytic activity, as seen above. The acetylated enzyme catalyzes the insertion of oxygen at position 15 of docosahexaenoic acid, but with R– rather than S-configuration. Therefore, DHA is converted to 17R-HpDHA, and not to 17S-HpDHA, and all the derived Protectins, called aspirin-triggered protectins or AT-protectins and synthesized according to the metabolic pathways described above, have the R configuration at position 17.
Examples are:

  • AT-PD1;
  • the racemic mixture of 10R/S,17R-diHDHA and 16R/S,17R-diHDHA;
  • 10S,17R-diHDHA.

Note: COX-2 can also catalyze the oxidation of arachidonic acid to form 15R-HETE. In turn 15R-HETE is converted to Lipoxins, the first lipid mediators to initiate the inflammation-resolution process.

DHA and D-series Resolvins

D-series Resolvins or RvDs are a family of molecules derived from docosahexaenoic acid and composed of six molecules designated RvD1 through RvD6. They show many beneficial effects such as anti-inflammatory, neuroprotective and proresolving actions.

D-Series Resolvins

D-series Resolvins have six double bonds of which, in RvD1 and RvD2, four are conjugated to form a E,E,Z,E and E,Z,E,E conjugated tetraene, respectively.
Another distinctive feature is that RvDs are, with the exclusion of RvD5 and RvD6, tri-hydroxylated molecules. Furthermore, like Protectins, they have a hydroxyl group at position 17, also in this case, due to the conversion of docosahexaenoic acid to the intermediate 17S-hydroxyperoxide-DHA, in a reaction catalyzed by 15-lipoxygenase, that is, Protectin and Resolvin synthesis pathways share the first step.
Below, the successive steps leading to the synthesis of the six D-series Resolvins.

  • 17S-HpDHA is reduced to 17S-hydroxy-DHA, in a reaction catalyzed by a peroxidase.
  • 17S-Hydroxy-DHA is converted to 4S-hydroperoxy, 17S-hydroxy-DHA and 7S-hydroperoxy, 17S-hydroxy-DHA, respectively. The reaction is catalyzed by 5-lipoxygenase.
  • In the next step, the two former intermediates are converted to 4S,5S-, and 7S,8S-epoxy-17S-hydroxy-DHA respectively. Epoxide synthesis is due to the 5-lipoxygenase epoxide generating activity.
  • The hydrolysis of the epoxides, catalyzed by a hydrolase, leads to the formation of the D-series Resolvin 1 to 4: respectively RvD1 and the epimer RvD2 from 7S,8S-epoxy-DHA and RvD3 and the RvD4 epimer from 4S,5S-epoxy-17S-hydroxy-DHA.
  • The synthesis of RvD5 and RvD6 follows a different route, that is, they are produced from 7S-hydroperoxy-17S-hydroxy-DHA and 4S-hydroperoxy-17S-hydroxy-DHA , respectively, in a peroxidase-catalyzed reaction.

Note: also EPA can be converted enzymatically to a family of molecules termed E-series Resolvins or RvEs. D and E nomenclatures derives from DHA and EPA, respectively.

Resolvin conjugates in tissue regeneration

As seen for Maresins and Protectins, D-series Resolvins can react with glutathione to form a family of molecules called Resolvin conjugates in tissue regeneration or RCTRs.

Resolvin Conjugates in Tissue Regeneration

Their synthesis seems to follow the same pattern as for MCTR and PCTR synthesis.
In the first step, the intermediate 7S,8S-epoxy-17S-hydroxy-DHA reacts with glutathione to form RCTR1 or 8R-glutathionyl-7S,17S-diHDHA or 8R-glutionyl,7S,17S-dihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid. The reaction is catalyzed by GST.
In the second step, the γ-glutamyl group is cleaved from RCTR1 to form RCTR2 or 16R-cysteinylglycinyl,7S,17S-diHDHA or 8R-cysteinylglycinyl,7S,17S-dihydroxy-4Z,9E,11E,13Z,15E,19Z -docosahexaenoic. The reaction is catalyzed by gamma-glutamyl transferase.
Finally, in a reaction catalyzed by dipeptidases, the cysteinyl-glycinyl bond of RCTR2 is cleaved to form the last member of the family: RCTR3 or 8R-cysteinyl,7S,17S-diHDHA or 8R-cysteinyl,7S,17S-dihydroxy -4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid.

Aspirin and Resolvins

Aspirin-acetylated COX-2 (see above) catalyzes the synthesis of 17R D-series Resolvins or aspirin-triggered (AT) resolvins, designated AT-RvD1 through AT-RvD6.
Such stereoisomers, as in the case of Maresin-L2, 14S,20R-diHDHA, 14R,21S-diHDHA and 14R,21R-diHDHA, can also derive from cytochrome P450 pathway.

Receptors for docosahexaenoic acid and its derivatives

As previously said, the effects of DHA can be mediated by the fatty acid itself as well as its metabolites.
Docosahexaenoic acid is a ligand of the nuclear receptor PPARα, but can also bind to the transmembrane protein G protein-coupled receptor 120 or GPR120, also known as Free fatty acid receptor 4 or FFAR4.
On the other hand, DHA metabolites are molecules that, after binding to specific cell membrane receptors, have a wide range of actions and act simultaneously at different sites and levels.
Here are some examples of receptors for D-Series Resolvins.

  • ALX/FRP2, with which RvD1 and AT-RvD1 interact;
  • G-protein coupled receptor 18 or GPR18 or RvD2 receptor or DRV1, to which RvD2 binds;
  • G-protein coupled receptor 32 or GPR32, also known as RvD1 receptor or DRV1, to which RvD1, its epimers At-RvD1, RvD3 and RvD5 bind.


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