Delta-6 Desaturase Enzyme aka "Δ6-Desaturase" or "D6-Desaturase" or
"FADS2" (Fatty Acid Desaturase-2)
Linoleic acid is the main dietary essential fatty acid (EFA). To be fully utilized by the body, it must be metabolized to a range of other substances. The first step in this pathway is Δ6 desaturase to gamma-linolenic acid (GLA). This step is slow and rate-limiting, particularly in humans. If Δ6-desaturation is impaired for any reason, the supply of further metabolites may be inadequate for normal function. If the consumption of further metabolites is excessive, then a normal rate of Δ6-desaturation may be inadequate. In these circumstances the direct supply of GLA or further metabolites may be of value. This concept is illustrated by atopic eczema and diabetes, which may represent inherited and acquired examples of inadequate Δ6-desaturation. The genes coding for Δ6 and Δ5 desaturase production have been located on human chromosome 11.
Δ6-desaturase is the rate-limiting step for transforming linoleic or linolenic acid into the longer EFA metabolites, GLA and EPA, respectively, and Δ6 is also used to make DHA out of EPA. Many people have less than optimal delta-6 activity. Infants have no appreciable Δ6 activity until about 6 months of age and must get DGLA, AA, EPA and DHA from breast milk and the diet. As we age, Δ6 activity declines progressively.
Dietary factors, including alcohol, trans-fats, and saturated fats will each inhibit Δ6 and, interestingly, so too will excessive dietary linolenic acid. Epstein Barr virus and HIV have been shown to inhibit the desaturases, and other viruses likely do the same. People experiencing post-viral fatigue syndrome have much lower levels of EFAs than controls.
Low Δ6-desaturase activity is known to occur in alcoholics, in those with allergic family history (atopic eczema and asthma), in PMS and premenstrual breast tenderness, in insulin-dependent diabetes, in insulin resistance and during fasting. In addition, a variety of cancer cell lines have demonstrated an inability to convert LA to GLA, which could be an important contributor to the pathogenesis of some forms of cancer. Low Δ6 activity can be identified by low levels of membrane DGLA, especially if the linoleic acid content is relatively higher. This scenario results in low levels of the series-1, anti-inflammatory prostaglandins, such as PGE1, made from DGLA.
Classically, this pattern is seen in children with atopic eczema: without PGE1 to control inflammation, eczema develops. But Δ6 is also used to make DHA, so relatively low levels of DHA and high levels of DPA or EPA may also indicate impaired Δ6 desaturase activity. Low levels of DHA have been associated with many neurological and psychological problems, including paresthesias, depression, dementia, and Alzheimer's disease. Researcher Donald Horrobin has speculated that the mechanism of damage in fetal alcohol syndrome may stem from the ability of alcohol to block Δ6 desaturase activity, resulting in inadequate production of prostaglandin E1 from DGLA and subsequent developmental abnormalities.
In
atopic eczema there might be a reduced rate of activity of the
enzyme Δ6-desaturase enzyme that converts linoleic acid to GLA and
a-linolenic acid to stearidonic acid. Such reduced activity
might be due to a mutation in the enzyme, altered expression
of the enzyme, a change in cofactors required for the enzyme, a
change in hormonal regulation, or the presence of enzyme
inhibitors. Investigators who happened to choose lard
or corn oil, preparations rich in primarily omega-6 EFAs, reported
consistently good results, with clinical improvement being
related to a rise in the iodine number of the blood.
In atopic dermatitis [eczema due to acute or chronic inflammatory reactions with a genetic basis] is associated with abnormally reduced omega-6 fatty acid levels (and decreased ceramide content). The hallmark of perturbed barrier function i.e., increased water loss from skin surface, is also seen here.
Δ6-desaturase is a component of a lipid metabolic pathway that converts the essential fatty acids linoleate and D-linolenate into long-chain polyunsaturated fatty acids. Isolation of Δ6-desaturase cDNA from human skin predicts an identical protein to that expressed in human brain and Southern analysis indicates a single locus, together suggestive of a single Δ6-desaturase gene. Within human skin, Δ6-desaturase mRNA and protein expression is restricted to differentiating sebocytes located in the suprabasal layers of the sebaceous gland. Enzymatic analysis using CHO cells overexpressing human Δ6-desaturase indicates catalysis of a "polyunsaturated fatty acid type" reaction, but also an unexpected "sebaceous-type" reaction, that of converting palmitate into the mono-unsaturated fatty acid sapienate, a 16-carbon fatty acid with a single cis double bond at the sixth carbon from the carboxyl end. Sapienate is the most abundant fatty acid in human sebum, and among hair-bearing animals is restricted to humans. This work identifies Δ6-desaturase as the major fatty acid desaturase in human sebaceous glands and suggests that the environment of the sebaceous gland permits catalysis of the sebaceous-type reaction and restricts catalysis of the polyunsaturated fatty acid type reaction. (SEE FULL TEXT)
One of the most common blocks in the prostaglandin chain involves Δ6-desaturase, the first step in the production of prostaglandins from essential fatty acids. When action of this enzyme is blocked, so is the entire pathway. This vital enzyme is inhibited first and foremost by trans fatty acids found in margarine, shortening and hydrogenated fats.These should be avoided at all costs. In addition, excess omega-6 fatty acids from modern commercial vegetable oils inhibit the pathway that leads to the Series 3 group. This is because both pathways begin with desaturation by the same Δ6-desaturase enzymes. Too much omega-6 in the diet "uses up" the Δ6-desaturase enzymes needed for the omega-3 pathway.
Deficiencies of biotin, vitamin E, protein, zinc, B12 and B6 all interfere with the action of Δ6-desaturase and other enzymes involved in prostaglandin production. B12 is found only in animal foods. B6 is also found chiefly in animal foods. It is highly sensitive to heat. Best sources are wheat germ, raw dairy products, raw fish and raw meat. Zinc absorption is inhibited by phytic acid in whole grains and legumes, particularly soy, that have not been properly prepared. Best sources of zinc are animal foods—red meat, organ meats and some sea foods such as oysters. Alcohol consumption interferes with Δ6-desaturase, as does malnutrition and overeating—so moderation is the key to tripping lightly down the prostaglandin pathway. There is some evidence that an excess of oleic acid (found chiefly in olive oil and nuts) may inhibit prostaglandin production. Even consumption of essential fatty acids should be restricted to about 4% of the diet. Excess of EFA's, especially omega-6 EFA's, can cause problems with both pathways. Excess consumption of sugar also interferes with the desaturating enzymes.
Diabetes, poor pituitary function and low thyroid function are synonymous with altered and inhibited Δ6-desaturase function.These ailments are often treated with evening primrose, borage or black current oils, which contain GLA, the Series 1 precursor. Dietary GLA can be used when production is blocked by defective Δ6-desaturase action. Fish oils provide EPA and DHA, the production of which is also blocked by poor Δ6-desaturase function. Supplements of evening primrose, borage or black current oils, and of fish liver oils are a good idea for everyone.
Diseases caused by altered Δ6-desaturase function include diabetes, alcoholism, cancer, premature aging, high cholesterol, Crohn's disease, cirrhosis of the liver, eczema, PMS, noncancerous breast disease, Sjogren's syndrome, scleroderma, ulcerative colitis and irritable bowel syndrome. In cancerous cells, all Δ6-desaturase activity is lost. GLA (from evening primrose, borage or black current oils) inhibits the growth of cancer cells but not of normal cells. The effectiveness of GLA compared to most drugs in treating not only cancer, but all of the diseases caused by inhibited Δ6-desaturase function, may explain the Food and Drug Administration's efforts to suppress the sale of evening primrose oil and similar products.
Polyunsaturated fatty acid (PUFA) utilization was investigated in skin fibroblasts cultured from a female patient with an inherited abnormality in lipid metabolism. These deficient human skin fibroblasts ("DF") converted 85;-95% less [1-14C]linoleic acid (18:2n-6) to arachidonic acid (20:4n-6), 95% less [3-14C]tetracosatetraenoic acid (24:4n-6) to docosapentaenoic acid (22:5n-6), and 95% less [1-14C]-linolenic acid (18:3n-3) and [3-14C]tetracosapentaenoic acid (24:5n-3) to docosahexaenoic acid (22:6n-3) than did normal human skin fibroblasts (NF). The only product formed by the DF cultures from [1-14C]tetradecadienoic acid (14:2n-6) was 18:2n-6. However, they produced 50;-90% as much 20:4n-6 as the NF cultures from [1-14C]hexadecatrienoic acid (16:3n-6), [1-14C]gamma-linolenic acid (18:3n-6), and [1-14C]dihomo-gamma-linolenic acid (20:3n-6), PUFA substrates that contain Delta6 double bonds. DF also contained 80% more 18:2n-6 and 25% less 20:4n-6. These results suggested that DF are deficient in Δ6-desaturase. This was confirmed by Northern blots demonstrating an 81;-94% decrease in Δ6-desaturase mRNA content in the DF cultures, whereas the Delta5-desaturase mRNA content was reduced by only 14%. This is the first inherited abnormality in human PUFA metabolism shown to be associated with a Δ6-desaturase deficiency. Furthermore, the finding that the 18- and 24-carbon substrates are equally affected suggests that a single enzyme carries out both Δ6-desaturase reactions in human PUFA metabolism.
A single gene encoding a Δ6-desaturase has been isolated and characterized in mammalian
species. This Δ6-desaturase plays a major role in the biosynthesis of PUFAs (polyunsaturated fatty acids). It
catalyses the rate-limiting desaturation of linoleic acid (C18:2 n−6) and α-linolenic acid (C18:3 n−3) required
for the biosynthesis of long-chain PUFAs. Moreover, recent studies have provided strong evidence that this Δ6-desaturase also acts on 24-carbon PUFAs of both the omega 6 ("n−6") and omega 3 ("n−3") series. Another substrate of
this Δ6-desaturase has been identified through complementary works from different investigators. This
Δ6-desaturase acts on a saturated fatty acid, palmitic acid (C16:0), leading to the newly characterized
biosynthesis of hexadecenoic acid (C16:1 n−10) or sapienate.
Conclusion: The Δ6-desaturase is considered as a key enzyme required
for numerous vital functions involving distinct PUFAs and
other PUFA-derived bioactive lipids. It seems that the
biological importance of Δ6-desaturase activity should also
be considered for its newly identified role in the control of
the biosynthesis of a monoenoic fatty acid (C16:1 n−10),
particularly in tissues with low Δ6-desaturase activity.
Important Co-factors: B-6, B-12, Biotin, Magnesium, Zinc, Vitamin E
Effect of magnesium deficiency on Δ6-desaturase activity and fatty acid composition of rat liver microsomes - National Institute of Health
Dual influence of aging and vitamin B6 deficiency on Δ6-desaturase of essential fatty acids in rat liver microsomes - National Institute of Health
The potential role of biotin insufficiency on essential fatty acid metabolism and cardiovascular disease risk - Elsevier
Patent Application Title: Delta 6-Desaturase Genes and Uses Thereof
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