Eicosanoid Metabolism

Medical Biochemistry

Lecture #50

METABOLISM OF UNSATURATED FATTY ACIDS

AND EICOSANOIDS • Animals have limited ability in desaturating

fatty acids.  • Dietary intake of certain polyunsaturated fatty

acids derived from a plant source is necessary. • These essential fatty acids give rise to

eicosanoic (C20) fatty acids, from which are derived families of compounds known as eicosanoids. 

• Eicosanoids include prostaglandins, thromboxanes, leukotrienes, and lipoxins. 

Some polyunsaturated fatty acids are essential:

• Double bonds are present in cis-configuration. • Palmitoleic and oleic acids are not essential in the

diet, because the tissues are capable of introducing a double bonds at the ∆9 position into the corresponding fatty acids. 

• In most mammals, double bonds can be introduced at the ∆4, ∆5, ∆6, and ∆9 positions but never beyond the ∆9 position. 

• Linoleic and -linolenic acids are known as nutritionally essential fatty acids. Arachidonic acid can be formed from linolenic acid in most mammals.

Monounsaturated fatty acids are synthesized by a ∆9

desaturase system: • Several tissues including the liver is responsible

for formation of monounsaturated fatty acids from saturated fatty acids. 

• ∆9 desaturase system in the endoplasmic reticulum will catalyze conversion of palmitoyl-CoA or stearoyl-CoA to palmitoleoyl-CoA or oleoyl-CoA, respectively. 

• The enzyme appear to be similar to cytochrome b5, and consists of three component proteins, NADH-cytochrome b5 reductase, cytochrome b5, and a cynamide-sensitive desaturase containing non-heme iron.

Synthesis of polyunsaturated fatty

acids involves desaturase and

elongase enzyme systems

 • In higher animals, additional double

bonds are introduced between the existing double bond and the carboxyl group. However, in plants they are introduced between the existing double bond and the (methyl terminal) carbon.

Linoleate may be converted to arachidonate

• Desaturation and chain elongation system is greatly diminished in the fasting state, upon glucagon and epinephrine administration, and in the absence of insulin as in type I diabetes mellitus.

Deficiency symptoms in the absence of essential fatty

acids from the diet: Nonlipid diet plus vitamins A and DRat ––––––––––––––––––––––––––––––––––– Reduced growth rate

and reproductive deficiency

• Deficiency syndrome was cured by the addition of linoleic, -linolenic, and arachidonic acids to the diet.

• Essential fatty acids are found in structural lipids of the cell and are concerned with structural integrity of mitochondrial membrane. 

• Arachidonic acid is present in membranes and accounts for 5-15% of the fatty acids in phospholipids.

• Docosahexaenoic acid (DHA; 3, 2:6) which is synthesized from -linolenic acid or obtained directly from fish oils, is present in high concentrations in retina, cerebral cortex, testis, and sperm. DHA is needed for development of the brain and retina and is supplied via the placenta and milk. 

• Patients with retinitis pigmentosa have low blood levels of DHA. Premature infants have a low ∆4 desaturase ability, reducing their potential for synthesizing DHA from n-3 fatty acids precursors. 

• In essential fatty acid deficiency, nonessential polyenoic acids of the w9 family replace the essential fatty acids in phospholipids, particularly with ∆5,8,11-eicosatrienoic acid. 

• The triene:tetraene ratio in plasma lipids can be used to diagnose the extent of essential fatty acid deficiency. 

• These fatty acids are found in high concentrations in vegetable oils.

Trans-fatty acids compete with cis-fatty acids

• Large amonuts of trans-unsaturated fatty acids in partially hydrogenated vegetable oils (e.g., margarine) raises the question of their safety as food additives. They are metabolized more like saturated than like the cis-unsaturated fatty acids. 

• Up to 15% of tissue fatty acids are in trans configuration. • Trans-polyunsaturated fatty acids do not possess

essential fatty acid activity and may antagonize the metabolism of essential fatty acids and enhance essential fatty acid deficiency. 

• Trans-fatty acids raise plasma LDL levels and lower HDL levels.

EICOSANOIDS: • Formed from C20 polyunsaturated fatty acids • Arachidonate and some other C20 give rise to

eicosanoids; prostaglandins (PG), thromboxanes (TX), leukotrienes (LT), and lipoxins (LX). 

• Eicosanoids are pharmacologically and physiologically active compounds. 

• Act as hormones functioning through G-protein linked receptors to elicit their biochemical effects.

CYCLOOXYGENASE pathway:

• Prostaglandin H synthase (PGHS) and two molecules of oxygen.

• There are two PGHS isoenzymes, PGHS-1 and PGHS-2. Each isoenzyme has cyclooxygenase and peroxidase activities.

• Each cell type produces only one type of prostanoid. 

• "Switching off" of prostaglandin formation is partly achieved by self-catalyzed destruction, i.e., it is a "suicide enzyme."

• Aspirin , a nonsteroidal anti-inflammatory drug (NSAID), inhibits cyclooxygenase of both PGHS-1 and PGHS-2 by acetylation.  

• Most other NSAIDs, such as indomethacin and ibuprofen, inhibit cyclooxygenases by competing with arachidonate.

• Transcription of PGHS-2 but not of PGHS-1 is completely inhibited by anti-inflammatory corticosteroids.

LIPOXYGENASE pathway:

• –Produce leukotrienes from eicosanoic acids in leukocytes, mastocytoma cells, platelets, and macrophages in response to both immunologic and nonimuunologic stimuli.

CLINICAL ASPECTS:• Infants receiving formula diets low in fat developed skin symptoms

that were cured by giving linoleate. • Patients maintained for long periods exclusively by intravenous

nutrition low in essential fatty acids. It can be prevented by an essential fatty acid intake of 1-2% of the total caloric requirement. 

• Abnormal metabolism of essential fatty acids has been noted in cystic fibrosis, acrodermatitis enteropathica, hepatorenal syndrome, Sjogren-Larsson syndrome, multisystem neuronal degeneration, Crohn's disease, cirrhosis and alcoholism, Zellweger's and Reye's syndrome. 

• Thromboxanes are synthesized in platelets and upon release cause vasoconstriction and platelet aggregation. Their synthesis is inhibited by low-dose aspirin.

• Prostaglandins (PGI2) are produced by blood vessel walls and are potent inhibitors of platelet aggregation.  

• Greenland Eskimos have low incidence of heart disease probably due to high intake of fish oils containing 20:5 3 (EPA, or eicosapentaenoic acid), which gives rise to the series 3 prostaglandins (PG3) and thromboxanes (TX3). PG3 and TX3 inhibit the release of arachidonate from phospholipids and the formation of PG2 and TX2.  

• Mixture of leukotrienes C4, D4, and E4 are 100-1000 times more potent than histamine or prostaglandins as a constrictor of the bronchial airway musculature. 

• Leukotrienes are vasoactive, and 5-lipoxygenase has been found in arterial walls.

CLINICAL ASPECTS (cont.)