Eicosapentaenoic acid

Last updated
Eicosapentaenoic acid
EPAnumbering.png
Eicosapentaenoic acid spacefill.png
Names
Preferred IUPAC name
(5Z,8Z,11Z,14Z,17Z)-Icosa-5,8,11,14,17-pentaenoic acid
Other names
(5Z,8Z,11Z,14Z,17Z)-5,8,11,14,17-eicosapentaenoic acid
Identifiers
3D model (JSmol)
3DMet
1714433
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.117.069 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C20H30O2/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-20(21)22/h3-4,6-7,9-10,12-13,15-16H,2,5,8,11,14,17-19H2,1H3,(H,21,22)/b4-3-,7-6-,10-9-,13-12-,16-15- Yes check.svgY
    Key: JAZBEHYOTPTENJ-JLNKQSITSA-N Yes check.svgY
  • InChI=1/C20H30O2/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-20(21)22/h3-4,6-7,9-10,12-13,15-16H,2,5,8,11,14,17-19H2,1H3,(H,21,22)/b4-3-,7-6-,10-9-,13-12-,16-15-
    Key: JAZBEHYOTPTENJ-JLNKQSITBZ
  • O=C(O)CCC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC
Properties
C20H30O2
Molar mass 302.451 g/mol
Hazards
GHS labelling:
GHS-pictogram-acid.svg
Danger
H314
P260, P264, P280, P301+P330+P331, P303+P361+P353, P304+P340, P305+P351+P338, P310, P321, P363, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Eicosapentaenoic acid (EPA; also icosapentaenoic acid) is an omega-3 fatty acid. In physiological literature, it is given the name 20:5(n-3). It also has the trivial name timnodonic acid. In chemical structure, EPA is a carboxylic acid with a 20-carbon chain and five cis double bonds; the first double bond is located at the third carbon from the omega end.

Contents

EPA is a polyunsaturated fatty acid (PUFA) that acts as a precursor for prostaglandin-3 (which inhibits platelet aggregation), thromboxane-3, and leukotriene-5 eicosanoids. EPA is both a precursor and the hydrolytic breakdown product of eicosapentaenoyl ethanolamide (EPEA: C 22 H 35 NO 2; 20:5,n-3). [1] Although studies of fish oil supplements, which contain both docosahexaenoic acid (DHA) and EPA, have failed to support claims of preventing heart attacks or strokes, [2] [3] [4] a recent multi-year study of Vascepa (ethyl eicosapentaenoate, the ethyl ester of the free fatty acid), a prescription drug containing only EPA, was shown to reduce heart attack, stroke, and cardiovascular death by 25% relative to a placebo in those with statin-resistant hypertriglyceridemia. [5] [6]

Sources

EPA is obtained in the human diet by eating oily fish, e.g., cod liver, herring, mackerel, salmon, menhaden and sardine, various types of edible algae, or by taking supplemental forms of fish oil or algae oil. It is also found in human breast milk.

Fish, like most vertebrates, can synthesize very little EPA from dietary alpha-linolenic acid (ALA). [7] Because of this extremely low conversion rate, fish primarily obtain it from the algae they consume. [8] It is available to humans from some non-animal sources (e.g., commercially, from Yarrowia lipolytica , [9] and from microalgae such as Nannochloropsis oculata, Monodus subterraneus, Chlorella minutissima and Phaeodactylum tricornutum , [10] [11] which are being developed as a commercial source). [12] EPA is not usually found in higher plants, but it has been reported in trace amounts in purslane. [13] In 2013, it was reported that a genetically modified form of the plant camelina produced significant amounts of EPA. [14] [15]

The human body converts a portion of absorbed alpha-linolenic acid (ALA) to EPA. ALA is itself an essential fatty acid, and humans need an appropriate supply of it. The efficiency of the conversion of ALA to EPA, however, is much lower than the absorption of EPA from food containing it. Because EPA is also a precursor to docosahexaenoic acid (DHA), ensuring a sufficient level of EPA on a diet containing neither EPA nor DHA is harder both because of the extra metabolic work required to synthesize EPA and because of the use of EPA to metabolize into DHA. Medical conditions like diabetes or certain allergies may significantly limit the human body's capacity for metabolization of EPA from ALA.

Forms

Commercially available dietary supplements are most often derived from fish oil and are typically delivered in the triglyceride, ethyl ester, or phospholipid form of EPA. There is debate among supplement manufacturers about the relative advantages and disadvantages of the different forms. One form found naturally in algae, the polar lipid form, has been shown to have improved bioavailability over the ethyl ester or triglyceride form. [16] Similarly, DHA or EPA in the lysophosphatidylcholine (LPC) form was found to be more efficient than triglyceride and phosphatidylcholines (PC) in a 2020 study. [17]

BaseEPA
Ethyl ester EPA ethyl ester
Lysophosphatidylcholine (LPC, or lysoPC)LPC-EPA, or lysoPC-EPA
Phosphatidylcholine (PC)EPA-PC
Phospholipid (PL)EPA-PL
Triglyceride (TG) or triacylglycerol (TAG)EPA-TG, or EPA-TAG
Re-esterified triglyceride (rTG), or re-esterified triacylglycerol (rTAG)EPA rTG, or r-TAG

Biosynthesis

Aerobic eukaryote pathway

EPA via aerobic eukaryote fatty acid synthesis Overview of biosynthesis of EPA.png
EPA via aerobic eukaryote fatty acid synthesis

Aerobic eukaryotes, specifically microalgae, mosses, fungi, and most animals (including humans), perform biosynthesis of EPA usually occurs as a series of desaturation and elongation reactions, catalyzed by the sequential action of desaturase and elongase enzymes. This pathway, originally identified in Thraustochytrium, applies to these groups: [18]

  1. a desaturation at the sixth carbon of alpha-linolenic acid by a Δ6 desaturase to produce stearidonic acid (SDA, 18:4 ω-3),
  2. elongation of the stearidonic acid by a Δ6 elongase to produce eicosatetraenoic acid (ETA, 20:4 ω-3),
  3. desaturation at the fifth carbon of eicosatetraenoic acid by a Δ5 desaturase to produce eicosapentaenoic acid (EPA, 20:5 ω-3),

Polyketide synthase pathway

a-linolenic acid to EPA via PKS LA--) EPA.pdf
α-linolenic acid to EPA via PKS

Marine bacteria and the microalgae Schizochytrium use an anerobic polyketide synthase (PKS) pathway to synthesize DHA. [18] The PKS pathway includes six enzymes namely, 3-ketoacyl synthase (KS), 2 ketoacyl-ACP-reductase(KR), dehydrase (DH), enoyl reductase (ER), dehydratase/2-trans 3-cos isomerase (DH/2,3I), dehydratase/2-trans, and 2-cis isomerase(DH/2,2I). The biosynthesis of EPA varies in marine species, but most of the marine species' ability to convert C18 PUFA to LC-PUFA is dependent on the fatty acyl desaturase and elongase enzymes. The molecule basis of the enzymes will dictate where the double bond is formed on the resulting molecule. [19]

The proposed polyketide synthesis pathway of EPA in Shewanella (a marine bacterium) is a repetitive reaction of reduction, dehydration, and condensation that uses acetyl coA and malonyl coA as building blocks. The mechanism of α-linolenic acid to EPA involves the condensation of malonyl-CoA to the pre-existing α-linolenic acid by KS. The resulting structure is converted by NADPH dependent reductase, KR, to form an intermediate that is dehydrated by the DH enzyme. The final step is the NADPH-dependent reduction of a double bond in trans-2-enoly-ACP via ER enzyme activity. The process is repeated to form EPA. [20]

Clinical significance

Salmon is a rich source of EPA. Roding, Iduns kokbok.jpg
Salmon is a rich source of EPA.

The US National Institute of Health's MedlinePlus lists medical conditions for which EPA (alone or in concert with other ω-3 sources) is known or thought to be an effective treatment. [21] Most of these involve its ability to lower inflammation.

Intake of large doses (2.0 to 4.0 g/day) of long-chain omega-3 fatty acids as prescription drugs or dietary supplements are generally required to achieve significant (> 15%) lowering of triglycerides, and at those doses the effects can be significant (from 20% to 35% and even up to 45% in individuals with levels greater than 500 mg/dL).

Dietary supplements containing EPA and DHA lower triglycerides in a dose dependent manner; however, DHA appears to raise low-density lipoprotein (the variant which drives atherosclerosis, sometimes inaccurately called "bad cholesterol") and LDL-C values (a measurement/estimate of the cholesterol mass within LDL-particles), while EPA does not. This effect has been seen in several meta-analyses that combined hundreds of individual clinical trials in which both EPA and DHA were part of a high dose omega-3 supplement, but it is when EPA and DHA are given separately that the difference can be seen clearly. [22] [23] For example, in a study by Schaefer and colleagues of Tufts Medical School, patients were given either 600 mg/day DHA alone, 600 or 1800 mg/day EPA alone, or placebo for six weeks. The DHA group showed a significant 20% drop in triglycerides and an 18% increase in LDL-C, but in the EPA groups modest drops in triglyceride were not considered statistically significant and no changes in LDL-C levels were found with either dose. [24]

Ordinary consumers commonly obtain EPA and DHA from foods such as fatty fish, [lower-alpha 1] fish oil dietary supplements, [lower-alpha 2] and less commonly from algae oil supplements [lower-alpha 3] in which the omega-3 doses are lower than those in clinical experiments. A Cooper Center Longitudinal Study that followed 9253 healthy men and women over 10 years revealed that those who took fish oil supplements did not see raised LDL-C levels. [25] In fact, there was a very slight decrease of LDL-C which was statistically significant but too small to be of any clinical significance. These individuals took fish oil supplements of their own choosing, and it should be recognized that the amounts and ratios of EPA and DHA vary according to the source of fish oil.

Omega-3 fatty acids, particularly EPA, have been studied for their effect on autistic spectrum disorder (ASD). Some have theorized that, since omega-3 fatty acid levels may be low in children with autism, supplementation might lead to an improvement in symptoms. While some uncontrolled studies have reported improvements, well-controlled studies have shown no statistically significant improvement in symptoms as a result of high-dose omega-3 supplementation. [26] [27]

In addition, studies have shown that omega-3 fatty acids may be useful for treating depression. [28] [29]

EPA and DHA ethyl esters (all forms) may be absorbed less well, thus work less well, when taken on an empty stomach or with a low-fat meal. [30]

Notes

  1. ↑ Cooked salmon contain 500–1,500 mg DHA and 300–1,000 mg EPA per 100 grams of fish. See page: Salmon as food.
  2. ↑ Omega-3 dietary oil supplements have no standard doses and generally salmon oil has more DHA than EPA while other white fishes have more EPA than DHA. One producer, Trident Food's Pure Alaska, for example reports per serving DHA 220 mg and EPA 180 mg for their salmon oil (total omega-3 = 600 mg), but DHA 144 mg and EPA 356 mg for pollock fish oil (total omega-3 = 530 mg). Equivalent products from another producer, Fish Oils, Puritan's Pride, reports DHA 180 mg and EPA 150 mg for their salmon oil product (total omega-3 = 420 mg), but DHA 204 mg and EPA 318 mg for fish oil derived from anchovy, sardine, and mackerel (total omega-3 = 600 mg). For information and comparison purposes only, no endorsements are implied.
  3. ↑ Many plant sources of omega-3s are rich in ALA but completely lack EPA and DHA. The exception is algae derived oils. Because there are more commercially-grown algae sources of DHA than EPA, algae omega-3 supplements typically contain more DHA than EPA. For example, Nordic Naturals reports per serving DHA 390 mg and EPA 195 mg (total omega-3 = 715 mg), Calgee reports DHA 300 mg and EPA 150 mg (total omega-3 = 550 mg) and so on, but iwi reports EPA 250 mg (total omega-3 = 254 mg). For information and comparison purposes only, no endorsements are implied.

Related Research Articles

Omega−3 fatty acids, also called Omega−3 oils, ω−3 fatty acids or n−3 fatty acids, are polyunsaturated fatty acids (PUFAs) characterized by the presence of a double bond, three atoms away from the terminal methyl group in their chemical structure. They are widely distributed in nature, being important constituents of animal lipid metabolism, and they play an important role in the human diet and in human physiology. The three types of omega−3 fatty acids involved in human physiology are α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). ALA can be found in plants, while DHA and EPA are found in algae and fish. Marine algae and phytoplankton are primary sources of omega−3 fatty acids. DHA and EPA accumulate in fish that eat these algae. Common sources of plant oils containing ALA include walnuts, edible seeds, and flaxseeds as well as hempseed oil, while sources of EPA and DHA include fish and fish oils, and algae oil.

Essential fatty acids, or EFAs, are fatty acids that humans and other animals must ingest because the body requires them for good health, but cannot synthesize them.

α-Linolenic acid Chemical compound

α-Linolenic acid, also known as alpha-linolenic acid (ALA), is an n−3, or omega-3, essential fatty acid. ALA is found in many seeds and oils, including flaxseed, walnuts, chia, hemp, and many common vegetable oils.

<span class="mw-page-title-main">Oily fish</span> Fish species with oils in their tissues and coelom

Oily fish are fish species with oil (fats) in soft tissues and in the coelomic cavity around the gut. Their fillets may contain up to 30% oil, although this figure varies both within and between species. Examples of oily fish include small forage fish such as sardines, herring and anchovies, and other larger pelagic fish such as salmon, trout, tuna, swordfish and mackerel.

gamma-Linolenic acid or GLA is an n−6, or omega-6, fatty acid found primarily in seed oils. When acting on GLA, arachidonate 5-lipoxygenase produces no leukotrienes and the conversion by the enzyme of arachidonic acid to leukotrienes is inhibited.

Krill oil is an extract prepared from a species of Antarctic krill, Euphausia superba. Processed krill oil is commonly sold as a dietary supplement. Two components of krill oil are omega-3 fatty acids similar to those in fish oil, and phospholipid-derived fatty acids (PLFA), mainly phosphatidylcholine.

Fish oil is oil derived from the tissues of oily fish. Fish oils contain the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), precursors of certain eicosanoids that are known to reduce inflammation in the body and improve hypertriglyceridemia. There has been a great deal of controversy in the 21st century about the role of fish oil in cardiovascular disease, with recent meta-analyses reaching different conclusions about its potential impact.

<span class="mw-page-title-main">Vegetarian nutrition</span> Nutritional and human health aspects of vegetarian diets

Vegetarian nutrition is the set of health-related challenges and advantages of vegetarian diets.

<span class="mw-page-title-main">Docosahexaenoic acid</span> Chemical compound

Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural 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 obtained directly from maternal milk, fatty fish, fish oil, or algae oil. The consumption of DHA contributes to numerous physiological benefits, including cognition. As the primary structural component of nerve cells in the brain, the function of DHA is to support neuronal conduction and to allow optimal function of neuronal membrane proteins.

Dihomo-γ-linolenic acid (DGLA) is a 20-carbon ω−6 fatty acid. In physiological literature, it is given the name 20:3 (ω−6). DGLA is a carboxylic acid with a 20-carbon chain and three cis double bonds; the first double bond is located at the sixth carbon from the omega end. DGLA is the elongation product of γ-linolenic acid. GLA, in turn, is a desaturation product of linoleic acid. DGLA is made in the body by the elongation of GLA, by an efficient enzyme which does not appear to suffer any form of (dietary) inhibition. DGLA is an extremely uncommon fatty acid, found only in trace amounts in animal products.

Fatty acid desaturases are a family of enzymes that convert saturated fatty acids into unsaturated fatty acids and polyunsaturated fatty acids. For the common fatty acids of the C18 variety, desaturases convert stearic acid into oleic acid. Other desaturases convert oleic acid into linolenic acid, which is the precursor to alpha-linolenic acid, gamma-linolenic acid, and eicosatrienoic acid.

<span class="mw-page-title-main">Essential fatty acid interactions</span>

There are many fatty acids found in nature. Two types of fatty acids considered essential for human health are the omega-3 and omega-6 types. These two essential fatty acids are necessary for some cellular signalling pathways and are involved in mediating inflammation, protein synthesis, and metabolic pathways in the human body.

Docosapentaenoic acid (DPA) designates any straight open chain polyunsaturated fatty acid (PUFA) which contains 22 carbons and 5 double bonds. DPA is primarily used to designate two isomers, all-cis-4,7,10,13,16-docosapentaenoic acid and all-cis-7,10,13,16,19-docosapentaenoic acid. They are also commonly termed n-6 DPA and n-3 DPA, respectively; these designations describe the position of the double bond being 6 or 3 carbons closest to the (omega) carbon at the methyl end of the molecule and is based on the biologically important difference that n-6 and n-3 PUFA are separate PUFA classes, i.e. the omega-6 fatty acids and omega-3 fatty acids, respectively. Mammals, including humans, can not interconvert these two classes and therefore must obtain dietary essential PUFA fatty acids from both classes in order to maintain normal health.

<span class="mw-page-title-main">Linoleoyl-CoA desaturase</span> Class of enzymes

Linoleoyl-CoA desaturase (also Delta 6 desaturase, EC 1.14.19.3) is an enzyme that converts between types of fatty acids, which are essential nutrients in the human body. The enzyme mainly catalyzes the chemical reaction

<span class="mw-page-title-main">Omega-3 acid ethyl esters</span>

Omega-3-acid ethyl esters are a mixture of ethyl eicosapentaenoic acid and ethyl docosahexaenoic acid, which are ethyl esters of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found in fish oil. Together with dietary changes, they are used to treat high blood triglycerides which may reduce the risk of pancreatitis. They are generally less preferred than statins, and use is not recommended by NHS Scotland as the evidence does not support a decreased risk of heart disease. Omega-3-acid ethyl esters are taken by mouth.

<span class="mw-page-title-main">Ethyl eicosapentaenoic acid</span> Medication

Ethyl eicosapentaenoic acid, sold under the brand name Vascepa among others, is a medication used to treat dyslipidemia and hypertriglyceridemia. It is used in combination with changes in diet in adults with hypertriglyceridemia ≥ 150 mg/dL. Further, it is often required to be used with a statin.

Omega-3 carboxylic acids (Epanova) is a formerly marketed yet still not an Food And Drug Administration (FDA) approved prescription medication–since taken off market by the manufacturer–used alongside a low fat and low cholesterol diet that lowers high triglyceride (fat) levels in adults with very high levels. This was the third class of fish oil-based drug, after omega-3 acid ethyl esters and ethyl eicosapentaenoic acid (Vascepa), to be approved for use as a drug. The first approval by US Food and Drug Administration was granted 05 May 2014. These fish oil drugs are similar to fish oil dietary supplements, but the ingredients are better controlled and have been tested in clinical trials. Specifically, Epanova contained at least 850 mg omega-3-acid ethyl esters per 1 g capsule.

In general, cognitive support diets are formulated to include nutrients that have a known role in brain development, function and/or maintenance, with the goal of improving and preserving mental processes such as attentiveness, short-term and long-term memory, learning, and problem solving. Currently, there is very little conclusive research available regarding cat cognition as standardized tests for evaluating cognitive ability are less established and less reliable than cognitive testing apparatus used in other mammalian species, like dogs. Much of what is known about feline cognition has been inferred from a combination of owner-reported behaviour, brain necropsies, and comparative cognitive neurology of related animal models. Cognition claims appear primarily on kitten diets which include elevated levels of nutrients associated with optimal brain development, although there are now diets available for senior cats that include nutrients to help slow the progression of age-related changes and prevent cognitive decline. Cognition diets for cats contain a greater portion of omega-3 fatty acids, especially docosahexaenoic acid (DHA) as well as eicosapentaenoic acid (EPA), and usually feature a variety of antioxidants and other supporting nutrients thought to have positive effects on cognition.

<span class="mw-page-title-main">Seaweed oil</span>

Seaweed oil, also called algae oil or algal oil, is used for making food, with the purified product almost colorless and odorless. It is also under development as a possible alternative fuel and manufacturing agent.

Frederick D. Sancilio is an American pharmaceutical scientist, research professor and serial entrepreneur best known for founding several biotechnology and contract research organizations including, Alcami, Endeavor Pharmaceuticals, Clearway Global, Omega Blu Supplements and Sancilio Pharmaceuticals. Sancilio has participated in the development of more than 40 drug product patents that have been granted by the United States Patent and Trademark Office.

References

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  3. ↑ O'Connor A (March 30, 2015). "Fish Oil Claims Not Supported by Research". The New York Times. Archived from the original on May 28, 2018. Retrieved October 11, 2015.
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  6. ↑ "Vascepa® (icosapent ethyl) 26% Reduction in Key Secondary Composite Endpoint of Cardiovascular Death, Heart Attacks and Stroke Demonstrated in REDUCE-IT™". November 10, 2018. Archived from the original on May 23, 2019. Retrieved January 21, 2019.
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  18. 1 2 Qiu, Xiao (2003-02-01). "Biosynthesis of docosahexaenoic acid (DHA, 22:6-4, 7,10,13,16,19): two distinct pathways". Prostaglandins, Leukotrienes and Essential Fatty Acids. 68 (2): 181–186. doi:10.1016/S0952-3278(02)00268-5. ISSN   0952-3278. PMID   12538082.
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