Palmitic acid elongation

The elongation reactions are repeated until the growing chain reaches 16 carbons in length (palmitic acid). 

Further chain elongation of palmitic acid occurs by reactions similar to those just described, but CoA rather than ACP is the carrier group, ancl separate enzymes are needed for each step rather than a multienzyme synthase complex. 

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 end-product of this process is the C-16 saturated fatty acid, palmitate. The elongation of palmitate to longer-chain fatty acids involves another system (see below). 

In the vertebrates, biosynthesis of fatty acids is catalyzed by fatty add synthase, a multifunctional enzyme. Located in the cytoplasm, the enzyme requires acetyl CoA as a starter molecule. In a cyclic reaction, the acetyl residue is elongated by one C2 unit at a time for seven cycles. NADPH+H is used as a reducing agent in the process. The end product of the reaction is the saturated Cie acid, palmitic acid. 

In liver mitochondria, palmitic acid, as its CoA ester, is lengthened by successive additions of acetyl CoA. There is also a liver microsomal enzyme capable of elongating saturated and unsaturated fatty acids by addition of acetyl CoA or malonyl CoA. 

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. 

From simple considerations of the dimensions of the molecules, it can be seen at once that they are greatly elongated in the direction perpendicular to the surface. Palmitic acid, with sixteen carbons ii the molecule, has a molecular volume of 300 c.c., and therefore the molecule has a volume of 495 cub. A. its cross-section as measured is 20 5 sq. A., so that its length (measured perpendicular to the surface) must be some 24 2 A., if the density in the films is the same as that in bulk. It must therefore be four or five times as long as thick. 

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). 

Elongation of palmitic acid and larger acids occurs with acetyl CoA units as the two-carbon donor. 

Continued condensation of malonyl-CoA with acetyl-CoA units is catalysed by fatty acid synthase, eventually leading to the 16-carbon palmitic acid (Figme 5.3) this is then released and may undergo separate elongation and/or unsaturation reactions, to yield other fatty acid molecules. The active form of fatty acid synthase is a dimer of identical subunits. 

Figure 1.8 shows the synthesis of fatty acids. This complex process is catalysed by the multienzymatic complex, fatty acid synthetase. This enzyme uses as substrates acetyl-coA and malonyl-coA to produce palmitic acid. Afterwards, palmitic acid, a saturated fatty acid of 16 carbon atoms, can be used to produce other fatty acids (Ratledge and Evans 1989). Fatty acids with more carbon units, such as estearic acid, are obtained by elongation of palmitic acid. 

If the Fatty Acid Synthetase Complex only makes palmitate where do the rest of the fatty acids come from Of course palmitate can be shortened by P-oxidation. For longer fatty acids there is a fatty acid elongation system localized on the ER. The same reactions occur as in the S)mthetase, but now have individual enzymes. Palmitate is first activated to palmitoyl-CoA. The enzymes prefer C-16 or less as... 

The net effect of these eight steps is to take two acetyl groups and combine them into a single four-carbon butyryl group. Further condensation of butyryl synthase with another malonyl ACP yields a six-carbon unit, and still further repetitions of the pathway add two more carbon atoms to the chain each time until the 16-carbon palmitic acid is reached. Further chain elongation of palmitic acid occurs by reactions similar to those just described, but acetyl CoA itself rather than malonyl ACP is the two-carbon donor. 

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 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. 

The first step in de novo fatty acid synthesis is the production of malonyl-CoA from acetyl-CoA and bicarbonate. This committed step is catalyzed by acetyl-CoA carboxylase present in the cytoplasm of liver cells and adipocytes. After replacement of the CoA residue in acetyl-CoA by ACP (acyl carrier protein), malonyl-ACP is used to convert acetyl-ACP to butyryl-ACP by the fatty acid synthase complex. In this multistep reaction, NADPH is used as donor of hydrogen atoms and CO2 is produced. Butyryl-ACP is subsequently elongated to hexanoyl-ACP by a similar process in which malonyl-ACP serves as donor of two carbon atoms required for lengthening of the growing acyl chain. This process is repeated until palmitic acid... 

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. 

A number of plants and phytochemicals have attracted attention for their ability to reduce many of the risk factors associated with cardiovascular disease. Research into these diseases has shown the relationship between lesions, fatty streaking and plaque formation in blood vessels and the development of strokes and myocardial infarctions. These effects are linked to levels of plasma lipids which comprise triglycerides, cholesterol and other fat substances. It is known that the biosynthesis of lipids involves the condensation of several molecules of acetylcoenzyme A and malonylcoenzyme A in a gradual process of elongation of the fatty acid chain involving the sequential addition of two carbon units giving rise to fatty acids such as lauric acid (12 carbons) and eventually to palmitic acid (16 carbons). Palmitic acid is the precursor... 

Palmitate is elongated and desaturated to produce a series of fatty acids. In the liver, palmitate and other newly synthesized fatty acids are converted to triacyl-glycerols that are packaged into VLDL for secretion. 

The biogenesis of n-alkanes in plants presents two points of considerable and novel interest firstly, chain construction. Alkyl chains are built up in plants, animals and microorganisms by sequential condensation of C2 units of acetate to yield fatty acid and related polyketides, but the fatty acid synthetase complexes involved rarely, if at all, catalyse chain elongation beyond compounds thus typically stearic acid CH3(CH2)i6COOH is the end product although palmitic acid (C ) is usually the... 

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... 

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