Docosahexaenoic acid (DHA): chemistry, sources, biosynthesis, and molecular mechanisms

Docosahexaenoic acid is a polyunsaturated fatty acid with 22 carbon atoms and six cis double bonds.[1]

In the human diet, the main sources are fish and seafood, particularly those from cold waters.[2]

Many animals, including humans, are able to synthesize it, albeit with highly variable efficiency, from alpha-linolenic acid, the precursor of the omega-3 polyunsaturated fatty acids.[3][4]

It is found primarily in cell membranes, esterified within phospholipids, and is therefore a structural component of the membranes themselves. It is particularly abundant in nerve cells, and in the brain it is the most abundant polyunsaturated fatty acid.[5][6]

Docosahexaenoic acid can provide numerous health benefits both through its direct action and by acting as a precursor for the synthesis of bioactive lipids such as maresins, protectins and D-series resolvins.[7]

Summary: Key Points

  • Structure and chemical properties: docosahexaenoic acid is an omega-3 polyunsaturated fatty acid that constitutes a fundamental structural element for cell membrane fluidity, especially in nervous and retinal tissues.
  • Dietary and origin sources: marine phytoplankton represents the primary source of its de novo synthesis, while cold-water fish and seafood constitute the main dietary sources for humans.
  • Endogenous biosynthesis: it is synthesized from alpha-linolenic acid through an enzymatic pathway of desaturation, elongation, and ultimately peroxisomal beta-oxidation, albeit with very limited conversion rates in humans.
  • Pro-resolving mediators (SPMs): it serves as a precursor for the synthesis of specialized pro-resolving mediators, which are crucial for the active resolution of inflammation.
  • Biological implications: it plays a vital role in the development and function of the nervous, visual, and immune systems.

Contents

Chemical properties

Docosahexaenoic acid has a molecular weight of 328.49 g/mol, a molecular formula of C22H32O2 and a shorthand notation of 22:6n-3.
According to IUPAC nomenclature, its systematic name is (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid; it is also known as cervonic acid, while a common abbreviation is DHA.[1]

Its conjugate base is known as docosahexaenoate, and this is the form in which, at physiological pH, the free fatty acid is found in biological systems, having a pKa of approximately 4.58.[8]

Structural formula of docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid with 22 carbon atoms and six cis double bonds.
Structural Formula of Docosahexaenoic Acid

The presence of six cis double bonds, at positions 4, 7, 10, 13, 16, and 19 from the carboxylic end, places docosahexaenoic acid in the group of unsaturated fatty acids. Furthermore, as the first double bond, counting from the methyl end, is at position 3, the molecule belongs to the group of omega-3 polyunsaturated fatty acids (omega-3 PUFA), or omega-3 fatty acids.[4]

As the carbon chain consists of 22 carbon atoms, DHA can be classified as a long-chain fatty acid, i.e. a fatty acid with a carbon chain, whether saturated or unsaturated, comprising between 13 and 22 carbon atoms. It is worth noting that, among the unsaturated fatty acids present in the human body in significant quantities, it is the one with the longest carbon chain and the greatest number of double bonds.[9]

It is insoluble in water. At room temperature, it appears as a pale yellow oily liquid, with a density of 0.93–0.95 g/mL.[10]
Its melting point is –44 °C (–47 °F; 229 K), while its boiling point is 446.7 °C (836.1 °F; 719.8 K).[1]

Chemical and physical properties of docosahexaenoic acid
Category Parameter Specifications Reference/Value
Identifiers IUPAC name Systematic name (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid
CAS number CAS database reference 6217-54-5
PubChem CID National Center for Biotechnology Information 444805
ChEBI ID EMBL-EBI Ontology CHEBI:28125
Chemical characteristics Molecular formula Elemental formula C22H32O2
Molecular weight Molar mass 328.49 g/mol
Structural characteristics Chemical class Fatty acid classification Long-chain fatty acid / Omega-3 polyunsaturated fatty acid
Structural notation Shorthand notation and pKa 22:6n-3 (pKa: ≈ 4.58)
Physical properties Water solubility Solubility Practically insoluble
Physical state Appearance, density, and transition points Light yellow oily liquid (density: 0.93–0.95 g/mL; m.p.: –44 °C; b.p.: 446.7 °C)

Dietary sources

The main dietary sources of docosahexaenoic acid for humans are fish and seafood, particularly fish from cold seas and those caught on the high seas, which accumulate this fatty acid as they move up the marine food chain. Fish-derived products, such as cod liver oil and fish eggs, are also excellent sources, while shellfish contain smaller amounts.[2]

Marine microalgae, or phytoplankton, represent the primary source of de novo synthesis and the only direct plant-based source. Oils with high DHA concentrations are extracted from microalgae such as Schizochytrium sp., and from there, DHA bioaccumulates up the food chain.[11][12]

All the values shown in the table are subject to variation depending on the fishing season, the animal’s diet, with substantial differences between wild and farmed specimens, and the methods of processing, storage, and cooking.[13]

Average docosahexaenoic acid content in different food sources
Category Food/Source DHA Content (mg/100 g)
Fresh fish Mackerel 1400–1570
Wild Atlantic salmon 1100–1450
Farmed Atlantic salmon 1000–1100
Atlantic herring 900–1100
Fresh bluefin tuna 800–990
Anchovies 750–900
Sardine 700–850
Fish-derived products Cod liver oil 10000–11000
Fish eggs (bottarga, caviar) 3400–3800
Canned tuna (drained) 100–300
Mollusks and crustaceans Squid and cuttlefish 400–480
Mussels 250–320
Shrimp 150–200
Algal/Plant sources Schizochytrium sp. oil 30000–40000

Biosynthesis

DHA is synthesized solely from precursors obtained from the diet. The synthetic pathway from α-linolenic acid (ALA) consists of seven reactions, six of which take place in the endoplasmic reticulum, while the last occurs in the peroxisomes.[4]

In the first reaction, ALA is desaturated to stearidonic acid (18:4n-3) in a reaction catalysed by delta-6 desaturase (EC 1.14.19.3).

Stearidonic acid is elongated to 20:4n-3 in a reaction catalyzed by elongase 5 (EC 2.3.1.199, as with the other elongases).

20:4n-3 is desaturated to eicosapentaenoic acid (EPA; 20:5n-3) in a reaction catalyzed by delta-5 desaturase (EC 1.14.19.44).

EPA is elongated to docosapentaenoic acid (DPA; 22:5n-3) in a reaction catalyzed by elongase 5 and/or elongase 2. It is not yet clear whether one or both of these elongases catalyze this reaction.

22:5n-3 is elongated to 24:5n-3 in a reaction catalyzed by elongase 2.

This is followed by the desaturation of 24:5n-3, catalyzed by delta-6 desaturase, to 24:6n-3.

24:6n-3 leaves the endoplasmic reticulum and enters the peroxisomes, where two carbon atoms are removed via β-oxidation to yield docosahexaenoic acid.[3]

Diagram of docosahexaenoic acid biosynthesis from alpha-linolenic acid in seven steps featuring elongase and desaturase enzymes and intermediates.
Biosynthesis of Docosahexaenoic Acid from Alpha-Linolenic Acid

DHA leaves the peroxisomes, returns to the endoplasmic reticulum, and is incorporated into membrane phospholipids.[9]

In humans, the conversion rate of ALA to DHA is low, ranging from 0% to 4%. Higher values, up to 9%, are observed in women of childbearing age, possibly due to the action of oestrogen on delta-6 desaturase.[14][15][16]

In certain marine microalgae, such as those belonging to the genera Pavlova and Isochrysis, in a marine heterotrophic eukaryote Thraustochyrium sp., and in the herbivorous marine teleost fish Siganus canaliculatus, a delta-4 desaturase is present which enables DHA to be synthesized directly from 22:5n-3.[17][18][19]

It should be noted that, in the absence of dietary ALA, all downstream omega-3 polyunsaturated fatty acids are considered conditionally essential fatty acids.[9]

Regulation

The synthesis of docosahexaenoic acid is influenced by factors that alter the catalytic activity of some of the enzymes involved, in particular delta-6 desaturase and elongase 2. Furthermore, as the enzymes that catalyse the production of DHA from ALA are shared with the pathways leading to the synthesis of omega-6, omega-7 and omega-9 polyunsaturated fatty acids, the different fatty acids compete for the same enzymes. At the enzymatic level, this competition would favor omega-3 fatty acids; however, due to the high linoleic acid content in the Western diet, the synthesis of omega-6 polyunsaturated fatty acids appears to be favored.[4][9]

Delta-6 desaturase

Delta-6 desaturase catalyzes both the oxidation of α-linolenic acid to stearidonic acid and the conversion of 24:5n-3 to 24:6n-3, the direct precursor of DHA. The first reaction represents the rate-limiting step of the entire metabolic pathway.[3][20]

Like delta-5 desaturase, this enzyme is inhibited by cholesterol, saturated fatty acids, trans fatty acids, alcohol, glucocorticoids, and adrenaline. Protein deficiency and complete fasting also reduce the activity of delta-6 desaturase, while partial calorie restriction and insulin increase it.[21]

Finally, competition between α-linolenic acid and 24:5n-3 for the enzyme could explain the reduction in DHA levels observed following the intake of α-linolenic acid above certain levels.[22]

The activity of both desaturases is reduced in cases of diabetes mellitus, hyperlipidemia, hypertension, and metabolic syndrome.[23]

It should be emphasized that in humans, the activities of delta-5 desaturase and delta-6 desaturase are low, with delta-5 desaturase being more active than delta-6 desaturase; consequently, the conversion of α-linolenic acid and linoleic acid into their respective metabolites may be insufficient to meet requirements under certain conditions, such as old age and disease.[3][24]

Elongase 2

The second elongation reaction catalyzed by elongase 2, from DPA to 24:5n-3, appears to reach saturation when α-linolenic acid, stearidonic acid or EPA are supplied via the diet, suggesting that the enzyme may play a crucial role in determining whether DHA synthesis can be increased through the diet.[25]

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

Alpha-linolenic acid, linoleic acid, and oleic acid are metabolized by the same set of desaturases and elongases. There is therefore competition for these enzymes. However, it appears that omega-3 fatty acids are metabolized preferentially over omega-6 fatty acids, and omega-6 fatty acids over omega-9 fatty acids, thus resulting in a preference sequence of omega-3 > omega-6 > omega-9.[9]

It should, however, be emphasized that in the Western diet, as well as in tissues, linoleic acid is much more abundant than α-linolenic acid, and this appears to favor the pathway leading to the synthesis of omega-6 polyunsaturated fatty acids over the others, although the conversion of linoleic acid to arachidonic acid is not particularly efficient either.[26]

Under physiological conditions, omega-9 polyunsaturated fatty acids are synthesized in minimal, negligible quantities. This is of great importance, as the presence of high levels of Mead acid (20:3n-9) in the bloodstream indicates a deficiency of essential fatty acids, namely omega-3 and omega-6 fatty acids. It should be noted that both the omega-3 and omega-6 families inhibit the synthesis of omega-9 polyunsaturated fatty acids.[4][27]

Sites of synthesis

The main site for DHA synthesis is the liver.
The synthesized molecule, secreted into the bloodstream, becomes available for uptake by other organs, such as the brain.[3][28]

Among nerve cells, namely neurons, astrocytes, microglia, and oligodendrocytes, only astrocytes are capable of synthesizing docosahexaenoic acid, while neurons, which are the cells that accumulate the highest levels of the molecule, cannot synthesize it due to a lack of desaturase activity.[29]
In astrocytes, the ability to synthesize docosahexaenoic acid is negatively influenced by the availability of the preformed molecule. Therefore, when the supply of the fatty acid is adequate, their biosynthetic activity contributes less to its accumulation in the brain.[5]

Cells of the cerebral microvascular endothelium, although capable of elongating and desaturating shorter-chain fatty acids up to C18, lack the ability to complete the final desaturation step in the synthesis of both DHA and 22:5n-6.[30]

Cellular and tissue distribution

In most cell membranes, docosahexaenoic acid accumulates preferentially in the two main amine-containing and structural membrane phospholipids: phosphatidylethanolamine and, to a lesser extent, phosphatidylcholine. This does not apply to all cells; in neuronal membranes, high concentrations of DHA are found in phosphatidylserine, a non-structural phospholipid.[5][6]

Like other PUFAs, DHA is predominantly esterified at the sn-2 position, while the sn-1 position is mainly occupied by saturated fatty acids, in particular stearic acid and palmitic acid.[31]

DHA is not distributed uniformly across different tissues and cells; consequently, based on the quantity present, two categories can be identified.

There are cells and tissues that contain elevated amounts of it, often accounting for almost 50% of the moles of all acyl chains. Examples include the outer segment of the retinal rods, sperm, and neurons. These cells contain such high levels of DHA that it is common to find phospholipids in which the molecule is present in both the sn-2 and sn-1 positions. In these locations, DHA levels are not influenced by diet.[32][33]

DHA is the most abundant polyunsaturated fatty acid in the brain, and these levels appear to be essential for optimal neuronal and retinal function. Its content increases during development, largely due to dietary or hepatic sources, although some synthesis may occur in astrocytes.[34]

There are also other cells and tissues that normally contain less than a few percent of all acyl chains. In these sites, docosahexaenoic acid is found mainly in the sn-2 position, and its levels can be modified by diet. It is therefore likely that the health benefits associated with the intake of this molecule originate from these sites.[35]

Docosahexaenoic acid and human health

The idea that DHA might have health benefits arose from research carried out in the early 1970s, which sought to explain why thrombotic diseases, and ischemic heart disease in particular, were rare among the Inuit of Greenland. According to the authors, the reason lay in their fish-based diet, rich in DHA and EPA, both of which were found in significant quantities in the blood of these populations.[36]

These observations sparked epidemiological research, cell culture studies, and dietary studies conducted on both animals and humans, investigating the link between DHA and EPA levels and human health.

The positive effects of docosahexaenoic acid have been observed in virtually every type of disease, and it is precisely the heterogeneity of these conditions that suggests its action takes place at a molecular level common to many cell types. Both direct effects of the fatty acid and indirect actions via its metabolites, of which over seventy have been described to date, have been implicated.[37]

DHA is capable of binding in its free form to G-protein-coupled membrane receptors, to the transmembrane protein GPR120, and to the nuclear receptor PPARα, while in its esterified form it influences membrane fluidity and the composition of membrane lipid rafts.[38][39]

Once released from phospholipids by the action of phospholipase A2, it acts, similarly to ARA, EPA, and DPA, as a substrate for the production of numerous bioactive lipid mediators, known as SPMs (specialized pro-resolving mediators), which are capable of intervening in a multitude of different conditions.[7][40]

Molecular mechanisms and synthesis of SPMs

Synthesized at the site of inflammation or tissue damage, they are produced in small quantities; some are associated with a specific tissue or cell type, while for others, synthesis involves more than one cell type, a process referred to as transcellular synthesis.[37] This class of lipid mediators comprises four families.

  • Lipoxins, the first SPMs to be discovered, are synthesized from arachidonic acid.
  • Maresins, protectins, and resolvins are synthesized from docosahexaenoic acid, as well as from EPA and DPA.[40][41][42]

Following binding to specific cellular receptors, they are capable of powerfully regulating the activity of target cells. For example, in the case of their action on inflammation, they regulate neutrophil infiltration, the production of cytokines and chemokines, and the clearance of apoptotic neutrophils by macrophages, thereby promoting a return to tissue homeostasis.[43]

It is worth noting that while ARA is the precursor of both pro-inflammatory lipid mediators and those that promote the resolution of inflammation, DHA, EPA, and DPA are precursors of lipid mediators with anti-inflammatory and cytoprotective actions, and therefore promote healing.[7]

The synthesis of these mediators follows a specific temporal pattern. In acute inflammation, it is in fact possible to identify a pro-inflammatory phase, characterized by the synthesis of leukotrienes and prostaglandins from arachidonic acid, and a resolution phase, during which lipoxins, maresins, protectins, and resolvins are synthesized.[44]

Time course of pro-inflammatory and pro-resolving lipid mediators derived from arachidonic acid, DHA, EPA, and DPA.
Temporal Dynamics of Pro-Inflammatory and Pro-Resolving Mediator Synthesis from ARA, DHA, EPA, and DPA

Docosahexaenoic acid may also undergo free-radical-mediated peroxidation to form metabolites, such as neuroprostanes and neuroketals, which can be produced and exert their effects practically anywhere and at various concentrations.[45]

Secretory phospholipases A2

Docosahexaenoic acid present at the site of injury may originate from the bloodstream or be released from the membrane phospholipids of the cells involved.

The amount of DHA present in the blood of healthy individuals is modest, accounting for 1.3–5% of total fatty acids; variations are attributable to differences in dietary intake. Within a few minutes of the initial injury, the circulating molecule reaches the site of the injury, leaves the bloodstream and becomes available for enzymatic conversion into maresins, resolvins, and protectins, which will then interact with the immune cells present at the site.[46][47]

The release of DHA from membrane phospholipids is due to the hydrolytic activity of secretory phospholipases A2, the first enzymes to be involved in the metabolism of docosahexaenoic acid. Secretory phospholipases A2 are a subfamily of phospholipases A2 (EC 3.1.1.4), a family of hydrolases comprising, in mammals, over thirty different enzymes, whose activation is triggered by a specific stimulus acting on the target cell. Secretory phospholipases A2 account for approximately one-third of all phospholipases A2 and catalyze the release of PUFAs from membrane phospholipids.[48][49]

Enzymatic pathways for the conversion of SPMs

The metabolism of docosahexaenoic acid requires the involvement of various enzymes which, while exercising strict stereochemical control, catalyze the synthesis of chiral molecules, and are therefore defined using the RS system.[41] The main enzymes involved belong to the lipoxygenase, cyclooxygenase, and hydrolase families, as well as cytochrome P450.

Lipoxygenases catalyze the formation of hydroperoxides through the insertion of oxygen in the S configuration. Specifically, these are 5-lipoxygenase (5-LOX; EC 1.13.11.34), 12-lipoxygenase (12-LOX; EC 1.13.11.31), and 15-lipoxygenase (15-LOX; EC 1.13.11.33). 15-LOX initiates the primary biosynthetic pathway leading to 17S-hydroperoxy-DHA, the common precursor for D-series resolvins and protectins, while 12-LOX initiates the conversion of DHA into maresins via 14S-hydroperoxy-DHA. 5-lipoxygenase and 12-lipoxygenase also possess epoxide-generating activity.[50]

Cyclooxygenase 2 (COX-2), together with COX-1, is one of the two isoforms of cyclooxygenases, enzymes that catalyze the synthesis of endoperoxides (both EC 1.14.99.1).
The activity of the two enzymes is influenced by aspirin, which causes the irreversible acetylation of a serine residue at the active site. The acetylation of COX-1 blocks enzymatic activity, thereby inhibiting the synthesis of thromboxanes and prostaglandins.
Conversely, the acetylation of COX-2 does not result in the inhibition of activity: the enzyme loses its cyclooxygenase activity but acquires an activity similar to that of 15-lipoxygenase. In fact, the acetylated enzyme, like cytochrome P450, catalyzes the insertion of oxygen at position 17, but with the opposite stereochemistry to that of lipoxygenases, i.e., R rather than S. Therefore, the product of the reaction is 17R-hydroperoxy-DHA rather than 17S-hydroperoxy-DHA, serving as the precursor for aspirin-triggered resolvins and aspirin-triggered protectins.[51][52]

Soluble epoxide hydrolase (sEH; EC 3.3.2.10) hydrolyzes a wide range of epoxides in mammals, participating in the enzymatic conversion steps required to generate fully functional vicinal diols.[53]

Several members of the cytochrome P450 superfamily are involved in the metabolism of docosahexaenoic acid. The isoforms belonging to families 1, 2, and 3 are predominantly epoxidases capable of acting on ARA and EPA as well, generating epoxy-DHA derivatives, while the isoforms belonging to family 4 are mainly omega-hydroxylases.[54]

Other enzymes involved include certain members of the glutathione S-transferase (GST; EC 2.5.1.18) family, gamma-glutamyl transferase (GGT; EC 2.3.2.2), and dipeptidases, which are specifically involved in the biosynthesis of peptide-lipid conjugated mediators.[55]

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Domande Frequenti

How does the conversion of alpha-linolenic acid to DHA occur?

The conversion of ALA to DHA occurs mainly in the liver via successive desaturations and elongations, ending with peroxisomal beta-oxidation. In humans, the conversion rate is very limited, ranging between 0.05% and 1% depending on biological sex and dietary intake.

What are the main dietary and primary sources of DHA?

The primary sources of DHA are marine phytoplankton microalgae, which synthesize the lipid de novo. Fatty cold-water fish, such as salmon, mackerel, and herring, accumulate it along the food chain, representing the main direct dietary source for humans.

How does DHA contribute to the resolution of inflammation?

DHA serves as a precursor for the enzymatic synthesis of specialized pro-resolving mediators (SPMs), such as resolvins, protectins, and maresins. These molecules halt neutrophil recruitment, promote cellular debris clearance, and stimulate active tissue regeneration.

Biochemistry and Metabolism