Palmitic acid desaturation

Macrolide aggregation pheromones produced by male cucujid beetles are derived from fatty acids. Feeding experiments with labeled oleic, linoleic, and palmitic acids indicate incorporation into the macrolide pheromone component [ 117 ]. The biosynthesis of another group of beetle pheromones, the lactones, involves fatty acid biosynthetic pathways. Japonilure and buibuilactone biosynthesized by the female scarab, Anomalajaponica, involves A9 desaturation of 16 and 18 carbon fatty acids to produce Z9-16 CoA and Z9-18 CoA,hydroxylation at carbon 8 followed by two rounds of limited chain shortening and cyclization to the lactone [118]. The hydroxylation step appears to be stereospecific [118]. 

FIGURE 3-7 Pathways for the interconversion of brain fatty acids. Palmitic acid (16 0) is the main end product of brain fatty acid synthesis. It may then be elongated, desaturated, and/or P-oxidized to form different long chain fatty acids. The monoenes (18 1 A7, 18 1 A9, 24 1 A15) are the main unsaturated fatty acids formed de novo by A9 desaturation and chain elongation. As shown, the very long chain fatty acids are a-oxidized to form a-hydroxy and odd numbered fatty acids. The polyunsaturated fatty acids are formed mainly from exogenous dietary fatty acids, such as linoleic (18 2, n-6) and a-linoleic (18 2, n-3) acids by chain elongation and desaturation at A5 and A6, as shown. A A4 desaturase has also been proposed, but its existence has been questioned. Instead, it has been shown that unsaturation at the A4 position is effected by retroconversion i.e. A6 unsaturation in the endoplasmic reticulum, followed by one cycle of P-oxidation (-C2) in peroxisomes [11], This is illustrated in the biosynthesis of DHA (22 6, n-3) above. In severe essential fatty acid deficiency, the abnormal polyenes, such as 20 3, n-9 are also synthesized de novo to substitute for the normal polyunsaturated acids. 

The principal monoenoic acids, oleic (C18 1) and palmitoleic (C16 1), are derived from blood lipids but about 30% of these acids are produced by microsomal enzymes (in the endoplasmic reticulum) in the secretory cells by desaturation of stearic and palmitic acids, respectively ... 

In contrast to the anaerobic pathway found in E. coli, the aerobic pathway in eukaryotic cells introduces double bonds after the saturated fatty acid has been synthesized. Stearoyl-CoA (18 0) is the major substrate for desaturation. Stearic acid is made by the fatty acid synthase as a minor product, the major product being palmitic acid, and is activated to its CoA derivative by acyl-CoA synthase. In eukaryotic cells an enzyme complex associated with the endoplasmic reticulum desaturates stearoyl-CoA to oleoyl-CoA (18 1A9). This remarkable reaction requires NADH and 02 and results in the formation of a double bond in the middle of an acyl chain with no activating groups nearby. The chemical mechanism for desaturation of long-chain acyl-CoAs remains unclear. 

Enzyme complexes occur in the endoplasmic reticulum of animal cells that desaturate at A5 if there is a double bond at the A8 position, or at A6 if there is a double bond at the A9 position. These enzymes are different from each other and from the A9-desaturase discussed in the previous section, but the A5 and A6 desaturases do appear to utilize the same cytochrome b5 reductase and cytochrome b5 mentioned previously. Also present in the endoplasmic reticulum are enzymes that elongate saturated and unsaturated fatty acids by two carbons. As in the biosynthesis of palmitic acid, the fatty acid elongation system uses malonyl-CoA as a donor of the two-carbon unit. A combination of the desaturation and elongation enzymes allows for the biosynthesis of arachidonic acid and docosahexaenoic acid in the mammalian liver. As an example, the pathway by which linoleic acid is converted to arachidonic acid is shown in figure 18.17. Interestingly, cats are unable to synthesize arachidonic acid from linoleic acid. This may be why cats are carnivores and depend on other animals to make arachidonic acid for them. Also note that the elongation system in the endoplasmic reticulum is important for the conversion of palmitoyl-CoA to stearoyl-CoA. 

In the melanogaster subgroup, the same enzyme Desatl seems to be involved in the first desaturation step of pheromone synthesis (Figure 4.7), even if the specificity concerning the desaturation is somewhat modified (for example, in D. erecta, stearic acid is used for the first desaturation, instead of palmitic acid as in other species). In other Drosophila species, other enzymes could be involved Desat2 in D. ananassae and another yet unknown desaturase in D. virilis. The position of the double bond on carbon 11 in the latter species could indicate either that the desaturase acts on C20 saturated fatty acid, or that it has another unknown specificity, resembling the unusual specificities of some lepidopteran desaturases. 

Palmitic acid may be converted to stearic acid (C1K 0) by elongation of the carbon chain. Desaturation of stearic acid produces oleic acid (C18 1 A9). Linoleic acid (Ci8 2A9,12), however, cannot be synthesized in mammalian tissues. Therefore, it is an essential fatty acid for animals and must be obtained from the diet it has two important metabolic roles. One is to maintain the fluid state of membrane lipids, lipoproteins, and storage lipids. The other role is as a precursor of arachidonic acid, which has a specialized role in the formation of prostaglandins (Sec. 13.9). 

The answer is d. (Murray, pp 230-267. Scriver, pp 2297-2326. Sack, pp 121-138. Wihon, pp 287-320.) In humans, the end product of fatty acid synthesis in the cytosol is palmitic acid. The specilicity of cytosolic multienzyme, single-protein fatty acid synthetase is such that once the C16 chain length is reached, a thioesterase clips off the fatty acid. Elongation as well as desaturation of de novo palmitate and fatty acids obtained from the diet occur by the action of enzymes in the membranes of the endoplasmic reticulum. 

The answer is c. (Klurray, pp 505-626. Scriver, pp 4029-4240. Sack, pp 121-138. Wilson, pp 287-320.) In mammals, arachidonic (5,8,11,15-eicosatetraenoic) acid can only be synthesized from essential fatty acids derived from the diet. Linoleic (9,12-octadecadienoic) acid produces arachidonic acid following two desaturations and chain elongation. While linolenic (9,12,15-octadecatrienoic) acid also is an essential fatty acid, desaturation and elongation produce 8,11,14,17-eicosatetraenoic acid, which is distinct from arachidonic acid. Oleic, palmitic, and stearic acids are all nonessential fatty acids that cannot give rise to arachidonic acids in mammals. 

The answer is b. (Murray, pp 505-626. Scriver, pp 5029-5250. Sack, pp 121-138. Wilson, pp 287-320.) The essential fatty acid linoleic acid, with 18 carbons and two double bonds at carbons 9 and 18 (C-18 2-A ) is desaturated to form a-linolenic acid (C-18 3-A ), which is sequentially elongated and desaturated to form eicosatrienoic acid (C-20 3-2 8,11,1+) arachidonic acid (C-20 4-A " ), respectively. Many of the eicosanoids (20-carbon compounds)—prostaglandins, thromboxanes, and leukotrienes—are derived from arachidonic acid. The scientific name of arachidonic acid is eicosatetraenoic acid. Arachidonic acid can only be synthesized from essential fatty acids obtained from the diet. Palmitic acid (C-16 0) and oleic acid (C-18 l-A" ) can be synthesized by the tissues. 

C-16) is formed. By elongation and desaturation, palmitic acid can be used as precursor for the production of most natural fatty acids in the human body. Humans lack enzymes to synthesize linoleic and linolenic acid. Hence, these two fatty acids are essential and must be supplied to the body in the diet. 

A9-desaturase is generally considered as a lipogenic enzyme. It catalyses the introduction of a A9 double bound on the acyl-chain of saturated fatty acids such as palmitic acid, which can be produced by FAS. The hepatic A9-desatur-ase is well-known (Heinemann and Ozols, 2003) since it has been purified more than 30 years ago (Strittmatter et al., 1974). This A9-desaturase acts on both palmitic acid (C16 0) and stearic acid (C18 0) to produce pamitoleic acid (C16 ln-7) and oleic acid (C18 ln-9) respectively (Fig. 1.1). Under normal dietary conditions. Cl6 1 n-7 and C18 ln-9 are the main fatty acids of the n-7 and n-9 families in animals. 

See also Acetyl-CoA, Fats, Albumin, Fatty Acid Activation, Oxidation of Saturated Fatty Acids, Oxidation of Unsaturated Fatty Acids, Fatty Acid Biosynthesis Strategy, Palmitate Synthesis from Acetyl-CoA, Fatty Acid Desaturation, Essential Fatty Acids, Control of Fatty Acid Synthesis, Molecular Structures and Properties of Lipids (from Chapter 10)... 

See also Fatty Acids, Table 10.1, Synthesis of Long Chain Fatty Acids, Fatty Acid Desaturation, Fatty Acid Synthase, Palmitate Synthesis from Acetyl-CoA... 

Acyl-CoAs are intermediates in oxidation of fatty acids, in fat synthesis, in elongation of fatty acids longer than palmitate (16 carbons), in fatty acid desaturation. 

Desaturation of fatty acids involves a process that requires molecular oxygen (O2), NADH, and cytochrome dj. The reaction, which occurs in the endoplasmic reticulum, results in the oxidation of both the fatty acid and NADH (Fig. 33.18). The most common desaturation reactions involve the placement of a double bond between carbons 9 and 10 in the conversion of palmitic acid to palmitoleic acid (16 1, A ) and the conversion of stearic acid to oleic acid (18 1, A ). Other positions that can be desaturated in humans include carbons 4, 5, and 6. 

Palmitic acid has been demonstrated to be metabolized utilizing different pathways than other fatty acids. For example, PA was found to be metabolized in human skeletal muscle cells in a mechanism quite different from that of oleic acid (Bakke et al., 2012). In addition, eellular uptake, the incorporation into cellular phospholipids, desaturation and oxidation of palmitic acid was found to differ from that of oleic, as well as stearic acids in hamster... 

Palmitic acid occupies a distinct place among the all FA diversity. This FA in one or another quantity present in every lipid class in all plant objects. Moreover virtually all FAs are derived from palmitic acid by its modification, namely desaturation, elongation, hydroxylation, oxidation, etc. Although fatty acids are major constituents of every membrane in a cell and are also found outside cells in the cuticular lipids, their major site of synthesis is within the plastid. In this regard, the process of lipid biosynthesis in plants is fundamentally different from that in animals and fimgi, which produce fatty acids primarily in the cytosol... 

The biosynthesis of FA occurs predominantly in the two subcellular compartments, chloroplasts and endoplasmic reticulum (ER) plant mitochondria also contribute to FA synthesis, but only in a very minor way. De novo synthesis of palmitic, stearic and FAs with shorter chain length and also the first desaturation step of saturated FAs e.g. palmitic acid to palmitoleic or stearic acid to oleic one occur in plastids, whereas the next desaturation steps occurs in the ER. [4,6],... 

Chloroplasts from photosynthetic tissues of higher plants and algae contain -3-hexadecenoate (8) (Fig. 2.13), an unusual palmitate-derived fatty acid. Desaturation of the 3-position requires light and may occur after the palmitic acid precursor is attached to the acyl moiety. This acid is found almost entirely at the 2-position of phosphatidyl glycerol (9) (Fig. 2.2). 

Fatty acid synthesis occurs in the cell cytoplasm and produces palmitic acid. The addition of two-carbon units to preformed long-and medium-chain fatty acids takes place at the endoplasmic reticulum, as does desaturation. However, mammals are incapable of introducing double bonds beyond carbon atom 9 (see Chapter 3). 

The fatty acid desaturation of liver microsomes was measured by estimation of the percentage conversion of l-l c linoleic acid (61 mC/mmole, 99% radiochemical purity, purchased from New England Nuclear Corp., Boston, Mass) to Y-linolenic acid and l-l c palmitic acid (55.5 mC/mmole, 99% radiochemical purity, purchased from the Radiochemical Centre, Amersham, England) to palmitoleic acid. Three nmoles of labeled acid and 97 nmoles of unlabeled acid were incubated aerobically with 5 mg microsomal protein and the necessary cofactors at 35°C during 20 min, according to the procedure described previously (Gomez Dumm et al, 1975). 

Fig. 1. Effect of propylthiouracil and thyroxine [ administration compared to controls LZ] on the oxidative desaturation of l-l c linoleic acid to y-linolenic acid (18 2->18 3) and palmitic acid to palmitoleic acid (16 0- 16 1). Results are means of analysis of 5 animals (each analysis was performed in duplicate). Vertical lines represents 1 SEM. Results corresponding to thyroxine-treated rats are significantly different from the controls (p<0.001).

The endoplasmic reticulum is a site for the introduction of double bonds ( desaturation ) into fatty acids. The pathway used is almost universal, having been identified in bacteria, yeasts, algae, higher plants, protozoa and animals. Examples are the conversion of stearic acid (18 0) to oleic acid (18 ln-9) and of palmitic acid (16 0) to palmitoleic acid (16 ln-7) by the insertion of a cis double bond between carbons 9 and 10. Because the double bond is inserted between carbons 9 and 10 counting from the carboxyl end of the acyl chain, the desaturase enzyme is known as delta-9 desaturase (A -desaturase), although sometimes this enzyme is referred to as stearoyl CoA (coenzyme A) desaturase. 

Figure 16.4 Long-chain and very long-chain fatty acid biosynthesis in mammals. The long-chain saturated fatty acids and unsaturated fatty acids of the n-10, n-7, and n-9 families (Top panel) can be synthesized from palmitic acid (Cl6 0) produced by the cellular fatty acid synthesis machinery. Long-chain fatty acids of the n-6 and n-3 famihes can only be synthesized from their respective precursors obtained from diets. The symbols of, , and stand for the involved activities of desaturation, elongation, and peroxisomal 3-oxidation, respectively, in the steps. Many isoforms of the genes corresponding to these activities were identified (see the review [34] for details).

The lipids which contain either saturated or unsaturated fatty acids at the n-2 position of their glycerol moieties are derived from phosphatidic acid synthesized within the chloroplast. The biosynthesis of lipids containing such a configuration is referred to as the prokaryotic pathway. The desaturation of palmitic acid to hexadecatrienoic acid is only observed in the prokaryotic pathway of the so-called plants. 

Our data suggest an inhibition of fatty acid biosynthesis between the elongation step of palmitic acid and the desaturation of oleic acid yielding linolenic acid. 

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